Cell cycle checkpoints (Homo sapiens)

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275, 89, 9446, 59, 91, 9721, 83, 848832, 50, 71, 93, 1005, 245, 14, 2423, 49, 55, 57, 81...857, 57, 8536588329, 5116, 34, 63653915, 60, 72, 901, 263827, 77889, 13, 79585130, 37, 42, 5471, 767, 8517, 56, 68, 92589929, 51, 701, 2644, 9243112, 28, 623533, 39, 69, 8022, 25361131, 57, 64, 74, 92...19, 87583, 8, 10, 75, 89...95593865658cytosolnucleoplasmCENPP CDKN1A RPS27 SEC13 UBC(381-456) p-T714,T734-BARD1 UBC(305-380) PAFAH1B1 CENPM CENPC1 DYNLL1 PLK1 KNTC1 p-WEE1MCM6 PolyUb-TP53 UBC(457-532) RCC2 ITGB3BP CENPI CENPQ CyclinA:Cdk2:p21/p27complexUBC(153-228) RAD9A UBA52(1-76) ANAPC11 UBC(1-76) HIST3H3 p-S166,S188-MDM2 NDE1 CLIP1 UBC(457-532) p-S346,S367,S403-MDM4 HIST1H2BL RFC3 RNF168 PSMD2 SPC25 PPP2R1B UBB(153-228) UBC(381-456) PSMB7 NUP43 KIF2C MCC:APC/C complexRANBP2 UBC(609-684) UBE2N HIST2H2BE MCM8 ZWINT ANAPC5 UBC(77-152) ADPCENPC1 RFWD2YWHAZ ORC1 SEH1L-1 NUP85 UBC(533-608) MCM8 RPS27 BRCC3 PPP2R1A NUP85 SKA2 CENPT 26S proteasomeYWHAB PSME1 PSMA8 CDC16 SEH1L-1 RANGAP1 RPA1 SKA1 PPP2CB HIST1H2BB PLK1 UBA52(1-76) SKA1 RPS27A(1-76) p-S15,S20-TP53Tetramer:ZNF385AMCM3 ZNF385A PSMD6 ORC2 CDC7 MIS12 PPP2R1A RANGAP1 MAD2L1 CDC20 SPDL1 SPDL1 UBB(1-76) PSMD14 ORC3 UBC(457-532) MCM3 CENPF PPP2R5C p-S216-CDC25C:14-3-3protein complexPPP2R5A p-S216-CDC25CATPANAPC10 BUB1B UBE2N CHEK1CDC26 UBE2C AHCTF1 Cdc45:CDK:DDK:Mcm10:Activated claspin:pre-replicative complexNDE1 BUB3 p-S1981,Ac-K3016-ATM MLF1IP CDK2 p-S403-MDM4 ORC3 ATPCCNB1 RAD9A Rad17-RFC complexbound to DNAp-S25,S1778-TP53BP1 MAD2L1CCNB:p-T14-CDK1CENPO p-S435-GTSE1PPP2R5D Ubp-S1387,S1423,S1524,S1547-BRCA1 DNADNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complexDYNLL1 Me2K21-HIST1H4 CDKN1A mRNA UIMC1 CENPE PSMB10 BIRC5 UBC(77-152) TP53 Mad1:kinetochorecomplexHIST1H2BJ ORC5 p-S435-GTSE1:PolyUb-TP53 TetramerDYNC1LI2 PPP2R1A PSME4 NUP160 PSMA5 RNF8 HIST1H2BD ADPPSMA6 CLASP1 ATPRAD9B NUP133 XPO1 CCNB1 ADPUBC(305-380) B9D2 CENPF UBC(381-456) ZW10 Kinetochore:Mad1:MAD2* ComplexKIF2C CDC20 p-S25,S1778-TP53BP1 CENPE UBC(609-684) SEC13 p-S15,S20-TP53 SKA2 PAFAH1B1 SFN CDKN1A geneUBC(229-304) CDCA8 UBC(77-152) CENPI Activated MAD2L1 UBC(1-76) PSME3 CENPQ UBC(381-456) NDEL1 HIST3H2BB DYNC1I2 DSN1 HIST1H2BJ CLIP1 p-S988,S1387,S1423,S1524,S1547-BRCA1 BUB3 BUB3 p-S15,S20-TP53 SPC24 CDCA8 XPO1 HIST3H3 Activated MAD2L1UBE2V2 DYNC1I1 PMF1 ATPUBB(153-228) MCM2 RFC4 UBE2E1 AURKB RANGAP1 CDC7 UBC(229-304) CDC20 XPO1 HIST1H2BO RFC3 RPS27 DNA2 HIST1H2BH PPP2R5C RFC2 ANAPC11 PolyUb-TP53 TetramerANAPC4 ORC6 CyclinE:CDK2:CDKN1A,CDKN1BAPITD1 CDC20 PPP1CC MIS12 SKA1 PAFAH1B1 ATPTP53 SPDL1 UBB(153-228) Persistent single-stranded DNA UBC(305-380) ANAPC2 DBF4 ATPp-5T-MDC1 PolyUb-TP53 TetramerCENPK CDC45 p-S166,S188-MDM2dimer,p-S166,S188-MDM2:MDM4ATR UBC(153-228) ANAPC7 CDKN1B TAOK1 WRN CDC27 UBC(77-152) UBE2C p-S166,S188-MDM2 ATPp-S102-WHSC1 SKA1 TOP3A PPP2R1B PPP2R1A DYNLL2 MDM4 RPA3 CDC27 ZNF385AATR CDK2 ERCC6L ATR:ATRIP:RPA:ssDNAsignaling complexNDEL1 YWHAQ p-T14,Y15,T161-CDK1 UBC(533-608) MLF1IP MCM7 cyclin Ub-p-S123-CDC25ANUP98-5 ubiquitinatedphospho-COP1(ser-387)KIF2A DYNC1H1 AHCTF1 PLK1 H2BFS CDK:DDK:MCM10:activepre-replicativecomplex:CDC45RFC5 PSMD10 YWHAZ DYNC1I2 ADPHUS1 NUP43 CLASP2 ADPPMF1 KNTC1 p-S343-NBN PPP2CB CDC16 CHEK2DYNC1LI1 CENPF MLF1IP PPP2R5D CENPP APITD1 p-S166,S188-MDM2:p-S403-MDM4CDC20 PPP2R5B UBC(381-456) NSL1 ZW10 CDC20 CDKN1A,CDKN1BDYNC1H1 p-S15-TP53 TetramerCLASP2 PPP2R5D KNTC1 UbCENPQ p-5S,T-MDM2Persistent single-stranded DNA Ubiquitin ligaseTAOK1 PPP1CC INCENP ADPSPC25 RPS27A(1-76) p-S166,S188-MDM2DYNC1I1 CENPM BUB3 MAD1L1 CDC20 PPP2R5E AURKB p-S387-RFWD2 ADPORC1 BIRC5 B9D2 CCNB2 ORC5 NUP85 ORC2 PPP2CA phosphorylatedanaphase promotingcomplex (APC/C)ITGB3BP ZWINT MAPRE1 KIF2B p-S15,S20-TP53Tetramer:ZNF385A:CDKN1A GeneSPC24 PSMD9 DYNLL1 UBE2V2 KIF18A PPP2CA RAD9B BUB1BHIST1H2BL PKMYT1NDC80 ADPBRE BABAM1 AURKB ADPDSN1 RPS27A(1-76) Kinetochore:Mad1:MAD2 ComplexUBC(533-608) CENPC1 UBB(1-76) PPP2R1B PPP2R5C PPP2R5B KIF2A BLM ADPMCM10 UBC(609-684) B9D2 UBA52(1-76) RAD9:HUS1:RAD1ATPUBB(77-152) CENPM KAT5 PLK1 SGOL2 RAD50 p-T68-CHEK2 ORC6 NUF2 NUDC CDC6 CENPN UBC(229-304) PSMD1 UBB(77-152) CENPA NDE1 KNTC1 CDKN1ABUB1B CDC26 ANAPC10 RMI1 PSMA2 PPP1CC cyclin p-S166,S188-MDM2 UBB(1-76) CDK2 UBC(1-76) AHCTF1 NSL1 PMF1 PPP2R5E NDEL1 p-S123-CDC25ACCNB:CDK1UBC(229-304) CCNA1 p-S166,S188-MDM2 CDK1 CENPI ANAPC2 p-S166,S188-MDM2 p-S1981,Ac-K3016-ATM TAOK1 NUP43 CKAP5 RPA2 BUB1 BUB3 CCNB1 DYNC1LI2 RPA3 DYNLL2 RAD9B RPA2 TP53 TetramerERCC6L p-S387-RFWD2CENPL RAD17 PSMC6 MCM7 ADPADPUBC(229-304) UBA52(1-76) MDM4 APITD1 CASC5 CDKN1B CENPN CDKN1A CCNE:CDK2CENPH DYNLL2 CDK2 PSMB5 MAD1L1 RAD9A SPC25 SGOL1 PolyUb-TP53 MRE11A Cdc45:CDK:DDK:Mcm10:claspin:pre-replicative complexp-S123-CDC25Aorigin of replication ATR:ATRIPCENPA BUB3ZWILCH SKA2 RAD1 UBC(533-608) ORC6 p-S166,S188-MDM2 UBC(457-532) RNF168 DNA Double StrandBreak ResponsePSMD3 DSN1 PolyUb,p-S166,S188-MDM2 DSN1 UBC(77-152) MCM10 MDM4 p-S166,S188-MDM2:p-S346,S367,S403-MDM4ATRIP PSMD12 ATPUBB(77-152) NUP37 HIST2H2BE PSMA4 CDC20p-S1387,S1423,S1524,S1547-BRCA1 UBB(153-228) PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4Zn2+ RHNO1 PPP2R5B CENPN MCM8 p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4DYNC1LI1 MIS12 RPA3 BUB1 KIF2B RPA3 HIST1H2BK ORC5 CDC25CCCNE1 RPA1 ANAPC15 MCM4 NUP133 BABAM1 ANAPC15 RFC4 RPA2 NUF2 UbDYNC1LI2 ATPNUF2 RMI2 PPP2R5A NUP107 RPS27A(1-76) ANAPC1 ITGB3BP p-S166,S188-MDM2dimer,p-S166,S188-MDM2,MDM4:TP53Persistent single-stranded DNA SEC13 PPP2R5A NUP133 p-S317,S345-CHEK1CDK2 NUP107 PolyUb-TP53 PPP2R5D KIF2A UBE2D1 DYNC1I1 p-S387-RFWD2:p-S15-TP53Me2K21-HIST1H4 CLIP1 RPA2 CCNA2 SPC24 PSMB3 p-S123-CDC25A MCM2 SEC13 CKAP5 UbCENPI ORC4 CENPO UBC(609-684) NUP98-5 ORC4 UBB(77-152) PSMD7 YWHAE CCNB1:p-T14,T161-CDK1NUP160 SFN K63PolyUb-K14,K16,p-S140-H2AFX NUP160 NDC80 CENPO HIST1H2BN PSMB1 CASC5 CENPC1 p-S435-GTSE1:PolyUb-TP53 TetramerRFC5 p-S343-NBN RPA1 CENPM ORC1 MAPRE1 RAD17:RFCMCM6 p-S166,S188-MDM2,MDM4CDKN1A gene PSMC3 ZWILCH PPP2CB RAD17 p-S,3T-CHEK2PPP2R5E CDKN1A RNF8 ANAPC16 ADPUBA52(1-76) p-S327,T847,T859-RBBP8 p-T68-CHEK2 dimerDBF4 p-S15,S20-TP53Tetramerp-T714,T734-BARD1 HIST1H2BB CLASP1 PPP2R5C p-T14-CDK1 BIRC5 MAD2*CDC20 complexCENPP RCC2 CLASP2 KinetochoreUBC(153-228) UBB(1-76) CENPP p-T916,S945-CLSPN UBC(1-76) DNADNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex:CHEK2YWHAH RPA1 ANAPC16 ADPSKA2 MAPRE1 YWHAB NUP98-5 p-S15-TP53 UBB(153-228) RANBP2 p14-ARF KAT5 MAPRE1 UBC(1-76) SGOL1 BUB1B PIAS4 BUB1 PSMA7 Rad9-Hus1-Rad1 boundto DNAp-S990,Ac-K1249-BRIP1 CDK2 ZW10 CENPT PPP2R5E RPA heterotrimerCASC5 MCM7 NUP37 HUS1 NUP160 MRE11A PSMB8 p-S406-FAM175A HIST1H2BC CHEK2 CDKN1B CCNB1 ADPPSMD8 NDC80 KAT5 NUP133 CENPL UBC(533-608) RANBP2 SPC25 BUB3 CLASP1 p-T4827,SUMO1-HERC2 MAD2L1 KIF2A UBB(77-152) ATPATPNUDC HIST1H2BA MCM4 HIST1H2BA KIF18A MCM6 CDCA8 CCNE2 PSMB2 UBC(609-684) CDCA8 PSMB6 PSMC2 ANAPC5 SEH1L-1 CLIP1 MAD1L1 NDE1 NSL1 PSMA1 CLSPNNUP107 UBC(153-228) TOPBP1 MAD1L1UBA52(1-76) NUP98-5 p-S387-RFWD2 RFC4 ADPSGOL2 Persistentsingle-stranded DNAPSME2 CENPA p-S435-GTSE1 YWHAQ RAD50 HIST1H2BM DNA double-strand break ends UBB(1-76) HIST1H2BK DYNC1H1 ATR:ATRIP:RPA:3'overhangingssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:RAD17:RFC:RAD9:HUS1:RAD1:RHNO1:TOPBP1TAOK1 14-3-3 dimerZWILCH INCENP Zn2+ PSMC5 RAD17 RPS27A(1-76) CENPK ZNF385A CENPQ HIST1H2BD UBC(229-304) Persistent single-stranded DNA ATPRPA complexed tossDNACENPK UBB(153-228) CLASP1 RCC2 MAD2L1 WEE1UBC(381-456) RANBP2 p-S435-GTSE1CCNA2 MIS12 HERC2-SUMO1 RPA1 ANAPC7 DYNC1I2 ATPADPDYNC1H1 SPC24 p-S166,S188-MDM2:MDM4NUDC PolyUb,p-S342,S367,S403-MDM4 RCC2 PCBP4CDC6 ATRIP hBUBR1:hBUB3:MAD2*:CDC20 complexDYNLL2 RFC3 3' overhanging DNA at resected DSB ends CENPF EXO1 KIF2B PSMD11 DYNC1I2 YWHAG ATPPHF20p-5T-MDC1 RFC5 p-S343-NBN MLF1IP RAD1 ADPUBC(305-380) UBB(77-152) NSL1 CDC25APCBP4:CDKN1A mRNAPIAS4 PPP2R5A YWHAH PSMB9 CENPH RFC5 HIST3H2BB HUS1 CASC5 RAD17 ADPANAPC1 HIST1H2BN p-T14,T161-CDK1 PSMA3 CLASP2 RPA2 Activated MAD2L1 RPA2 NUP107 p-S406-FAM175A UBC(77-152) UBC(609-684) PCBP4 origin of replication ZW10 ZWINT CENPT p-S1981,Ac-K3016-ATMHIST1H2BC INCENP p-S435-GTSE1 CDK2 B9D2 RANGAP1 PSMB4 UBC(457-532) PPP1CC PSMC4 CENPE HERC2-SUMO1 RPS27 PSMD13 p-S166,S188-MDM2 CENPO PSMD5 p-S216-CDC25CBUB1 CENPE p-S15-TP53 ZWINT RFC3 MCM10 NUP85 p-S15,S20-TP53 CDC23 DYNC1I1 MAD1L1 CDKN1A mRNAorigin of replication RAD50 ANAPC4 PSMD4 p-T68-CHEK2Activated MAD2L1 SGOL1 CENPN ATPBRE HIST1H2BO MCM2 KIF18A PPP2R1B RPS27A(1-76) DNA double-strand break ends INCENP CDC6 UBC(305-380) ATRIP p-T714,T734-BARD1 CENPH CKAP5 MRE11A H2BFS NUF2 MDM4 cyclin p-S1981,Ac-K3016-ATM RPA3 CKAP5 PPP2CB YWHAE DYNLL1 CCNA1 MCM5 SGOL2 MCM4 NDEL1 BRCC3 PPP2CA MCM5 ORC4 PPP2R5B CENPL p-S387-RFWD2p-S216-CDC25C CDC45 NUP43 KIF18A UBC(153-228) K63PolyUb-K14,K16,p-S140-H2AFX DYNC1LI1 SEH1L-1 CENPT BUB1B PSMC1 CCNA:CDK2CENPL BUB1B MDM4 XPO1 UBB(1-76) ATR MAD2L1 PSMB11 p-S102-WHSC1 RFC2 AURKB CDC7 UIMC1 ERCC6L RFC2 ATPPolyUb-TP53 UBC(1-76) DYNC1LI2 UBE2E1 NUP37 SPDL1 ERCC6L CDC45 NUP37 SGOL2 AHCTF1 CDC23 Activated MAD2L1 RPA1 HIST1H2BH CCNE2 ORC3 RPA3 YWHAG UBC(305-380) KIF2C RFC2 MCM5 CENPK PPP2CA CENPA CCNE1 ORC2 NDC80 ATPCENPH KIF2B KIF2C APITD1 ZWILCH HIST1H2BM UBC(457-532) CCNB1:p-T14,Y15,T161-CDK1PMF1 UBC(533-608) CCNB2 BIRC5 RAD1 SGOL1 NUDC DYNC1LI1 UBC(153-228) CLSPN MCM3 SHFM1 ITGB3BP PSMF1 PAFAH1B1 UBE2D1 p-T4827,SUMO1-HERC2 DBF4 BUB1B RFC4 4861131, 64, 74, 9853, 7840, 54, 73, 8252184, 4156, 68858356, 68, 925160, 66, 90384571, 7618, 474820965112067


Description

A hallmark of the human cell cycle in normal somatic cells is its precision. This remarkable fidelity is achieved by a number of signal transduction pathways, known as checkpoints, which monitor cell cycle progression ensuring an interdependency of S-phase and mitosis, the integrity of the genome and the fidelity of chromosome segregation.

Checkpoints are layers of control that act to delay CDK activation when defects in the division program occur. As the CDKs functioning at different points in the cell cycle are regulated by different means, the various checkpoints differ in the biochemical mechanisms by which they elicit their effect. However, all checkpoints share a common hierarchy of a sensor, signal transducers, and effectors that interact with the CDKs.<p>The stability of the genome in somatic cells contrasts to the almost universal genomic instability of tumor cells. There are a number of documented genetic lesions in checkpoint genes, or in cell cycle genes themselves, which result either directly in cancer or in a predisposition to certain cancer types. Indeed, restraint over cell cycle progression and failure to monitor genome integrity are likely prerequisites for the molecular evolution required for the development of a tumor. Perhaps most notable amongst these is the p53 tumor suppressor gene, which is mutated in >50% of human tumors. Thus, the importance of the checkpoint pathways to human biology is clear. View original pathway at:Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 69620
Reactome-version 
Reactome version: 61
Reactome Author 
Reactome Author: Hoffmann, Ingrid, Khanna, Kum Kum, Walworth, Nancy, Yen, Tim, O'Donnell, Michael

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Bibliography

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  40. Chang LF, Zhang Z, Yang J, McLaughlin SH, Barford D.; ''Molecular architecture and mechanism of the anaphase-promoting complex.''; PubMed Europe PMC Scholia
  41. Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC, Lukas J, Jackson SP.; ''ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks.''; PubMed Europe PMC Scholia
  42. Lakin ND, Hann BC, Jackson SP.; ''The ataxia-telangiectasia related protein ATR mediates DNA-dependent phosphorylation of p53.''; PubMed Europe PMC Scholia
  43. Griffith JD, Lindsey-Boltz LA, Sancar A.; ''Structures of the human Rad17-replication factor C and checkpoint Rad 9-1-1 complexes visualized by glycerol spray/low voltage microscopy.''; PubMed Europe PMC Scholia
  44. Byun TS, Pacek M, Yee MC, Walter JC, Cimprich KA.; ''Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint.''; PubMed Europe PMC Scholia
  45. Li M, Luo J, Brooks CL, Gu W.; ''Acetylation of p53 inhibits its ubiquitination by Mdm2.''; PubMed Europe PMC Scholia
  46. Wilson KA, Stern DF.; ''NFBD1/MDC1, 53BP1 and BRCA1 have both redundant and unique roles in the ATM pathway.''; PubMed Europe PMC Scholia
  47. Sudakin V, Chan GK, Yen TJ.; ''Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2.''; PubMed Europe PMC Scholia
  48. Monte M, Benetti R, Buscemi G, Sandy P, Del Sal G, Schneider C.; ''The cell cycle-regulated protein human GTSE-1 controls DNA damage-induced apoptosis by affecting p53 function.''; PubMed Europe PMC Scholia
  49. Montagnoli A, Fiore F, Eytan E, Carrano AC, Draetta GF, Hershko A, Pagano M.; ''Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation.''; PubMed Europe PMC Scholia
  50. Dalal SN, Schweitzer CM, Gan J, DeCaprio JA.; ''Cytoplasmic localization of human cdc25C during interphase requires an intact 14-3-3 binding site.''; PubMed Europe PMC Scholia
  51. Melchionna R, Chen XB, Blasina A, McGowan CH.; ''Threonine 68 is required for radiation-induced phosphorylation and activation of Cds1.''; PubMed Europe PMC Scholia
  52. Luo X, Tang Z, Rizo J, Yu H.; ''The Mad2 spindle checkpoint protein undergoes similar major conformational changes upon binding to either Mad1 or Cdc20.''; PubMed Europe PMC Scholia
  53. Shieh SY, Ahn J, Tamai K, Taya Y, Prives C.; ''The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites.''; PubMed Europe PMC Scholia
  54. Bochkareva E, Belegu V, Korolev S, Bochkarev A.; ''Structure of the major single-stranded DNA-binding domain of replication protein A suggests a dynamic mechanism for DNA binding.''; PubMed Europe PMC Scholia
  55. Chehab NH, Malikzay A, Stavridi ES, Halazonetis TD.; ''Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage.''; PubMed Europe PMC Scholia
  56. Peters JM.; ''The anaphase-promoting complex: proteolysis in mitosis and beyond.''; PubMed Europe PMC Scholia
  57. Khanna KK, Keating KE, Kozlov S, Scott S, Gatei M, Hobson K, Taya Y, Gabrielli B, Chan D, Lees-Miller SP, Lavin MF.; ''ATM associates with and phosphorylates p53: mapping the region of interaction.''; PubMed Europe PMC Scholia
  58. Blackwell LJ, Borowiec JA.; ''Human replication protein A binds single-stranded DNA in two distinct complexes.''; PubMed Europe PMC Scholia
  59. Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ, Mak TW.; ''DNA damage-induced activation of p53 by the checkpoint kinase Chk2.''; PubMed Europe PMC Scholia
  60. el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B.; ''WAF1, a potential mediator of p53 tumor suppression.''; PubMed Europe PMC Scholia
  61. Sharp DA, Kratowicz SA, Sank MJ, George DL.; ''Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein.''; PubMed Europe PMC Scholia
  62. Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B.; ''Amplification of a gene encoding a p53-associated protein in human sarcomas.''; PubMed Europe PMC Scholia
  63. Raderschall E, Golub EI, Haaf T.; ''Nuclear foci of mammalian recombination proteins are located at single-stranded DNA regions formed after DNA damage.''; PubMed Europe PMC Scholia
  64. Hopkins KM, Wang X, Berlin A, Hang H, Thaker HM, Lieberman HB.; ''Expression of mammalian paralogues of HRAD9 and Mrad9 checkpoint control genes in normal and cancerous testicular tissue.''; PubMed Europe PMC Scholia
  65. Fuchs SY, Adler V, Buschmann T, Wu X, Ronai Z.; ''Mdm2 association with p53 targets its ubiquitination.''; PubMed Europe PMC Scholia
  66. Blasina A, de Weyer IV, Laus MC, Luyten WH, Parker AE, McGowan CH.; ''A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase.''; PubMed Europe PMC Scholia
  67. Lieberman HB, Hopkins KM, Nass M, Demetrick D, Davey S.; ''A human homolog of the Schizosaccharomyces pombe rad9+ checkpoint control gene.''; PubMed Europe PMC Scholia
  68. Boyd SD, Tsai KY, Jacks T.; ''An intact HDM2 RING-finger domain is required for nuclear exclusion of p53.''; PubMed Europe PMC Scholia
  69. Parker LL, Piwnica-Worms H.; ''Inactivation of the p34cdc2-cyclin B complex by the human WEE1 tyrosine kinase.''; PubMed Europe PMC Scholia
  70. Fang G, Yu H, Kirschner MW.; ''The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation.''; PubMed Europe PMC Scholia
  71. Lee CH, Chung JH.; ''The hCds1 (Chk2)-FHA domain is essential for a chain of phosphorylation events on hCds1 that is induced by ionizing radiation.''; PubMed Europe PMC Scholia
  72. Chen J, Marechal V, Levine AJ.; ''Mapping of the p53 and mdm-2 interaction domains.''; PubMed Europe PMC Scholia
  73. Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; PubMed Europe PMC Scholia
  74. Zou L, Elledge SJ.; ''Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.''; PubMed Europe PMC Scholia
  75. Cheng Q, Chen L, Li Z, Lane WS, Chen J.; ''ATM activates p53 by regulating MDM2 oligomerization and E3 processivity.''; PubMed Europe PMC Scholia
  76. McGowan CH, Russell P.; ''Human Wee1 kinase inhibits cell division by phosphorylating p34cdc2 exclusively on Tyr15.''; PubMed Europe PMC Scholia
  77. Scoumanne A, Cho SJ, Zhang J, Chen X.; ''The cyclin-dependent kinase inhibitor p21 is regulated by RNA-binding protein PCBP4 via mRNA stability.''; PubMed Europe PMC Scholia
  78. Niida H, Nakanishi M.; ''DNA damage checkpoints in mammals.''; PubMed Europe PMC Scholia
  79. Galaktionov K, Beach D.; ''Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: evidence for multiple roles of mitotic cyclins.''; PubMed Europe PMC Scholia
  80. Cai Z, Chehab NH, Pavletich NP.; ''Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase.''; PubMed Europe PMC Scholia
  81. Pereg Y, Shkedy D, de Graaf P, Meulmeester E, Edelson-Averbukh M, Salek M, Biton S, Teunisse AF, Lehmann WD, Jochemsen AG, Shiloh Y.; ''Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage.''; PubMed Europe PMC Scholia
  82. Sørensen CS, Syljuåsen RG, Lukas J, Bartek J.; ''ATR, Claspin and the Rad9-Rad1-Hus1 complex regulate Chk1 and Cdc25A in the absence of DNA damage.''; PubMed Europe PMC Scholia
  83. Maki CG.; ''Oligomerization is required for p53 to be efficiently ubiquitinated by MDM2.''; PubMed Europe PMC Scholia
  84. Cheng Q, Cross B, Li B, Chen L, Li Z, Chen J.; ''Regulation of MDM2 E3 ligase activity by phosphorylation after DNA damage.''; PubMed Europe PMC Scholia
  85. Ball HL, Myers JS, Cortez D.; ''ATRIP binding to replication protein A-single-stranded DNA promotes ATR-ATRIP localization but is dispensable for Chk1 phosphorylation.''; PubMed Europe PMC Scholia
  86. Ellison V, Stillman B.; ''Biochemical characterization of DNA damage checkpoint complexes: clamp loader and clamp complexes with specificity for 5' recessed DNA.''; PubMed Europe PMC Scholia
  87. Iftode C, Daniely Y, Borowiec JA.; ''Replication protein A (RPA): the eukaryotic SSB.''; PubMed Europe PMC Scholia
  88. Wang W, Nacusi L, Sheaff RJ, Liu X.; ''Ubiquitination of p21Cip1/WAF1 by SCFSkp2: substrate requirement and ubiquitination site selection.''; PubMed Europe PMC Scholia
  89. Cordeiro-Stone M, Makhov AM, Zaritskaya LS, Griffith JD.; ''Analysis of DNA replication forks encountering a pyrimidine dimer in the template to the leading strand.''; PubMed Europe PMC Scholia
  90. Wu X, Bayle JH, Olson D, Levine AJ.; ''The p53-mdm-2 autoregulatory feedback loop.''; PubMed Europe PMC Scholia
  91. Wang B, Matsuoka S, Carpenter PB, Elledge SJ.; ''53BP1, a mediator of the DNA damage checkpoint.''; PubMed Europe PMC Scholia
  92. Zhao H, Watkins JL, Piwnica-Worms H.; ''Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints.''; PubMed Europe PMC Scholia
  93. Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMed Europe PMC Scholia
  94. Bernardi R, Liebermann DA, Hoffman B.; ''Cdc25A stability is controlled by the ubiquitin-proteasome pathway during cell cycle progression and terminal differentiation.''; PubMed Europe PMC Scholia
  95. Das S, Raj L, Zhao B, Kimura Y, Bernstein A, Aaronson SA, Lee SW.; ''Hzf Determines cell survival upon genotoxic stress by modulating p53 transactivation.''; PubMed Europe PMC Scholia
  96. Dornan D, Shimizu H, Mah A, Dudhela T, Eby M, O'rourke K, Seshagiri S, Dixit VM.; ''ATM engages autodegradation of the E3 ubiquitin ligase COP1 after DNA damage.''; PubMed Europe PMC Scholia
  97. Chaturvedi P, Eng WK, Zhu Y, Mattern MR, Mishra R, Hurle MR, Zhang X, Annan RS, Lu Q, Faucette LF, Scott GF, Li X, Carr SA, Johnson RK, Winkler JD, Zhou BB.; ''Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway.''; PubMed Europe PMC Scholia
  98. Hupp TR, Lane DP.; ''Allosteric activation of latent p53 tetramers.''; PubMed Europe PMC Scholia
  99. Lovly CM, Yan L, Ryan CE, Takada S, Piwnica-Worms H.; ''Regulation of Chk2 ubiquitination and signaling through autophosphorylation of serine 379.''; PubMed Europe PMC Scholia
  100. Bochkareva E, Korolev S, Lees-Miller SP, Bochkarev A.; ''Structure of the RPA trimerization core and its role in the multistep DNA-binding mechanism of RPA.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
117674view12:00, 22 May 2021EweitzModified title
114649view16:11, 25 January 2021ReactomeTeamReactome version 75
113097view11:16, 2 November 2020ReactomeTeamReactome version 74
112331view15:25, 9 October 2020ReactomeTeamReactome version 73
101230view11:12, 1 November 2018ReactomeTeamreactome version 66
100768view20:39, 31 October 2018ReactomeTeamreactome version 65
100312view19:16, 31 October 2018ReactomeTeamreactome version 64
99858view15:59, 31 October 2018ReactomeTeamreactome version 63
99415view14:35, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93868view13:42, 16 August 2017ReactomeTeamreactome version 61
93434view11:23, 9 August 2017ReactomeTeamreactome version 61
86525view09:20, 11 July 2016ReactomeTeamreactome version 56
83240view10:28, 18 November 2015ReactomeTeamVersion54
81345view12:52, 21 August 2015ReactomeTeamVersion53
76816view08:03, 17 July 2014ReactomeTeamFixed remaining interactions
76806view14:21, 16 July 2014ReactomeTeamFixed remaining interactions
76805view14:20, 16 July 2014ReactomeTeamFixed remaining interactions
76520view11:45, 16 July 2014ReactomeTeamFixed remaining interactions
75853view09:50, 11 June 2014ReactomeTeamRe-fixing comment source
75848view06:23, 11 June 2014Anwesha
75553view10:34, 10 June 2014ReactomeTeamReactome 48 Update
74908view13:43, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74552view08:35, 30 April 2014ReactomeTeamReactome46
69041view17:52, 8 July 2013MaintBotUpdated to 2013 gpml schema
44985view14:33, 6 October 2011MartijnVanIerselOntology Term : 'cell cycle checkpoint pathway' added !
42014view21:50, 4 March 2011MaintBotAutomatic update
39786view22:54, 18 January 2011KhanspersModified categories
39716view02:47, 14 January 2011AlexanderPicoAdded link to pathway
39714view02:35, 14 January 2011AlexanderPicoSpecify description
39703view02:08, 14 January 2011AlexanderPicoadded segmented line example
39702view01:54, 14 January 2011AlexanderPicoNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
14-3-3 dimerComplexR-HSA-1445138 (Reactome)
26S proteasomeComplexR-HSA-68819 (Reactome)
3' overhanging DNA at resected DSB ends R-NUL-75156 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AHCTF1 ProteinQ8WYP5 (Uniprot-TrEMBL)
ANAPC1 ProteinQ9H1A4 (Uniprot-TrEMBL)
ANAPC10 ProteinQ9UM13 (Uniprot-TrEMBL)
ANAPC11 ProteinQ9NYG5 (Uniprot-TrEMBL)
ANAPC15 ProteinP60006 (Uniprot-TrEMBL)
ANAPC16 ProteinQ96DE5 (Uniprot-TrEMBL)
ANAPC2 ProteinQ9UJX6 (Uniprot-TrEMBL)
ANAPC4 ProteinQ9UJX5 (Uniprot-TrEMBL)
ANAPC5 ProteinQ9UJX4 (Uniprot-TrEMBL)
ANAPC7 ProteinQ9UJX3 (Uniprot-TrEMBL)
APITD1 ProteinQ8N2Z9 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
ATR ProteinQ13535 (Uniprot-TrEMBL)
ATR:ATRIP:RPA:3'

overhanging

ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:RAD17:RFC:RAD9:HUS1:RAD1:RHNO1:TOPBP1
ComplexR-HSA-5685039 (Reactome)
ATR:ATRIP:RPA:ssDNA signaling complexComplexR-HSA-176281 (Reactome) While the ATR-ATRIP complex binds only poorly to RPA complexed with ssDNA lengths of 30 or 50 nt, binding is significantly enhanced in the presence of a 75 nt ssDNA molecule. Complex formation is primarily mediated by physical interaction between ATRIP and RPA. Multiple elements within the ATRIP molecule can bind to the RPA-ssDNA complex, including residues 1-107 (highest affinity), 218-390, and 390-791 (lowest afiinity). Although the full-length ATRIP is unable to bind ssDNA, an internal region (108-390) can weakly bind ssDNA when present in rabbit reticulocyte lysates. ATR can bind to the ssDNA directly independent of RPA, but this binding is inhibited by ATRIP. Upon binding, the ATR kinase becomes activated and can directly phosphorylate substrates such as Rad17.
ATR:ATRIPComplexR-HSA-176269 (Reactome) The ATR (ATM- and rad3-related) kinase is an essential checkpoint factor in human cells. In response to replication stress (i.e., stresses that cause replication fork stalling) or ultraviolet radiation, ATR becomes active and phosphorylates numerous factors involved in the checkpoint response including the checkpoint kinase Chk1. ATR is invariably associated with ATRIP (ATR-interacting protein) in human cells. Depletion of ATRIP by siRNA causes a loss of ATR without affecting ATR mRNA levels indicating that complex formation stabilizes ATR. ATRIP is also a substrate for the ATR kinase, but this modification does not play a significant role in the recruitment of ATR-ATRIP to sites of damage, the activation of Chk1, or the modification of p53.
ATRIP ProteinQ8WXE1 (Uniprot-TrEMBL)
AURKB ProteinQ96GD4 (Uniprot-TrEMBL)
Activated MAD2L1 ProteinQ13257 (Uniprot-TrEMBL)
Activated MAD2L1ProteinQ13257 (Uniprot-TrEMBL)
B9D2 ProteinQ9BPU9 (Uniprot-TrEMBL)
BABAM1 ProteinQ9NWV8 (Uniprot-TrEMBL)
BIRC5 ProteinO15392 (Uniprot-TrEMBL)
BLM ProteinP54132 (Uniprot-TrEMBL)
BRCC3 ProteinP46736 (Uniprot-TrEMBL)
BRE ProteinQ9NXR7 (Uniprot-TrEMBL)
BUB1 ProteinO43683 (Uniprot-TrEMBL)
BUB1B ProteinO60566 (Uniprot-TrEMBL)
BUB1BProteinO60566 (Uniprot-TrEMBL)
BUB3 ProteinO43684 (Uniprot-TrEMBL)
BUB3ProteinO43684 (Uniprot-TrEMBL)
CASC5 ProteinQ8NG31 (Uniprot-TrEMBL)
CCNA1 ProteinP78396 (Uniprot-TrEMBL)
CCNA2 ProteinP20248 (Uniprot-TrEMBL)
CCNA:CDK2ComplexR-HSA-141608 (Reactome)
CCNB1 ProteinP14635 (Uniprot-TrEMBL)
CCNB1:p-T14,T161-CDK1ComplexR-HSA-170073 (Reactome)
CCNB1:p-T14,Y15,T161-CDK1ComplexR-HSA-170065 (Reactome)
CCNB2 ProteinO95067 (Uniprot-TrEMBL)
CCNB:CDK1ComplexR-HSA-170077 (Reactome)
CCNB:p-T14-CDK1ComplexR-HSA-170069 (Reactome)
CCNE1 ProteinP24864 (Uniprot-TrEMBL)
CCNE2 ProteinO96020 (Uniprot-TrEMBL)
CCNE:CDK2ComplexR-HSA-68374 (Reactome)
CDC16 ProteinQ13042 (Uniprot-TrEMBL)
CDC20 ProteinQ12834 (Uniprot-TrEMBL)
CDC20ProteinQ12834 (Uniprot-TrEMBL)
CDC23 ProteinQ9UJX2 (Uniprot-TrEMBL)
CDC25AProteinP30304 (Uniprot-TrEMBL)
CDC25CProteinP30307 (Uniprot-TrEMBL)
CDC26 ProteinQ8NHZ8 (Uniprot-TrEMBL)
CDC27 ProteinP30260 (Uniprot-TrEMBL)
CDC45 ProteinO75419 (Uniprot-TrEMBL)
CDC6 ProteinQ99741 (Uniprot-TrEMBL)
CDC7 ProteinO00311 (Uniprot-TrEMBL)
CDCA8 ProteinQ53HL2 (Uniprot-TrEMBL)
CDK1 ProteinP06493 (Uniprot-TrEMBL)
CDK2 ProteinP24941 (Uniprot-TrEMBL)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45
ComplexR-HSA-68564 (Reactome)
CDKN1A ProteinP38936 (Uniprot-TrEMBL)
CDKN1A gene ProteinENSG00000124762 (Ensembl)
CDKN1A geneGeneProductENSG00000124762 (Ensembl)
CDKN1A mRNA ProteinENST00000244741 (Ensembl)
CDKN1A mRNARnaENST00000244741 (Ensembl)
CDKN1A,CDKN1BComplexR-HSA-182558 (Reactome)
CDKN1AProteinP38936 (Uniprot-TrEMBL)
CDKN1B ProteinP46527 (Uniprot-TrEMBL)
CENPA ProteinP49450 (Uniprot-TrEMBL)
CENPC1 ProteinQ03188 (Uniprot-TrEMBL)
CENPE ProteinQ02224 (Uniprot-TrEMBL)
CENPF ProteinP49454 (Uniprot-TrEMBL)
CENPH ProteinQ9H3R5 (Uniprot-TrEMBL)
CENPI ProteinQ92674 (Uniprot-TrEMBL)
CENPK ProteinQ9BS16 (Uniprot-TrEMBL)
CENPL ProteinQ8N0S6 (Uniprot-TrEMBL)
CENPM ProteinQ9NSP4 (Uniprot-TrEMBL)
CENPN ProteinQ96H22 (Uniprot-TrEMBL)
CENPO ProteinQ9BU64 (Uniprot-TrEMBL)
CENPP ProteinQ6IPU0 (Uniprot-TrEMBL)
CENPQ ProteinQ7L2Z9 (Uniprot-TrEMBL)
CENPT ProteinQ96BT3 (Uniprot-TrEMBL)
CHEK1ProteinO14757 (Uniprot-TrEMBL)
CHEK2 ProteinO96017 (Uniprot-TrEMBL)
CHEK2ProteinO96017 (Uniprot-TrEMBL)
CKAP5 ProteinQ14008 (Uniprot-TrEMBL)
CLASP1 ProteinQ7Z460 (Uniprot-TrEMBL)
CLASP2 ProteinO75122 (Uniprot-TrEMBL)
CLIP1 ProteinP30622 (Uniprot-TrEMBL)
CLSPN ProteinQ9HAW4 (Uniprot-TrEMBL)
CLSPNProteinQ9HAW4 (Uniprot-TrEMBL)
Cdc45:CDK:DDK:Mcm10:Activated claspin:pre-replicative complexComplexR-HSA-176182 (Reactome)
Cdc45:CDK:DDK:Mcm10:claspin:pre-replicative complexComplexR-HSA-176229 (Reactome)
Cyclin

A:Cdk2:p21/p27

complex
ComplexR-HSA-187926 (Reactome)
Cyclin E:CDK2:CDKN1A,CDKN1BComplexR-HSA-68376 (Reactome)
DBF4 ProteinQ9UBU7 (Uniprot-TrEMBL)
DNA

DNA

DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex:CHEK2
ComplexR-HSA-5683737 (Reactome)
DNA

DNA

DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex
ComplexR-HSA-5683605 (Reactome)
DNA Double Strand Break ResponsePathwayR-HSA-5693606 (Reactome) DNA double strand break (DSB) response involves sensing of DNA DSBs by the MRN complex which triggers ATM activation. ATM phosphorylates a number of proteins involved in DNA damage checkpoint signaling, as well as proteins directly involved in the repair of DNA DSBs. For a recent review, please refer to Ciccia and Elledge, 2010.
DNA double-strand break ends R-NUL-75165 (Reactome)
DNA2 ProteinP51530 (Uniprot-TrEMBL)
DSN1 ProteinQ9H410 (Uniprot-TrEMBL)
DYNC1H1 ProteinQ14204 (Uniprot-TrEMBL)
DYNC1I1 ProteinO14576 (Uniprot-TrEMBL)
DYNC1I2 ProteinQ13409 (Uniprot-TrEMBL)
DYNC1LI1 ProteinQ9Y6G9 (Uniprot-TrEMBL)
DYNC1LI2 ProteinO43237 (Uniprot-TrEMBL)
DYNLL1 ProteinP63167 (Uniprot-TrEMBL)
DYNLL2 ProteinQ96FJ2 (Uniprot-TrEMBL)
ERCC6L ProteinQ2NKX8 (Uniprot-TrEMBL)
EXO1 ProteinQ9UQ84 (Uniprot-TrEMBL)
H2BFS ProteinP57053 (Uniprot-TrEMBL)
HERC2-SUMO1 ProteinP63165 (Uniprot-TrEMBL)
HIST1H2BA ProteinQ96A08 (Uniprot-TrEMBL)
HIST1H2BB ProteinP33778 (Uniprot-TrEMBL)
HIST1H2BC ProteinP62807 (Uniprot-TrEMBL)
HIST1H2BD ProteinP58876 (Uniprot-TrEMBL)
HIST1H2BH ProteinQ93079 (Uniprot-TrEMBL)
HIST1H2BJ ProteinP06899 (Uniprot-TrEMBL)
HIST1H2BK ProteinO60814 (Uniprot-TrEMBL)
HIST1H2BL ProteinQ99880 (Uniprot-TrEMBL)
HIST1H2BM ProteinQ99879 (Uniprot-TrEMBL)
HIST1H2BN ProteinQ99877 (Uniprot-TrEMBL)
HIST1H2BO ProteinP23527 (Uniprot-TrEMBL)
HIST2H2BE ProteinQ16778 (Uniprot-TrEMBL)
HIST3H2BB ProteinQ8N257 (Uniprot-TrEMBL)
HIST3H3 ProteinQ16695 (Uniprot-TrEMBL)
HUS1 ProteinO60921 (Uniprot-TrEMBL)
INCENP ProteinQ9NQS7 (Uniprot-TrEMBL)
ITGB3BP ProteinQ13352 (Uniprot-TrEMBL)
K63PolyUb-K14,K16,p-S140-H2AFX ProteinP16104 (Uniprot-TrEMBL)
KAT5 ProteinQ92993 (Uniprot-TrEMBL)
KIF18A ProteinQ8NI77 (Uniprot-TrEMBL)
KIF2A ProteinO00139 (Uniprot-TrEMBL)
KIF2B ProteinQ8N4N8 (Uniprot-TrEMBL)
KIF2C ProteinQ99661 (Uniprot-TrEMBL)
KNTC1 ProteinP50748 (Uniprot-TrEMBL)
Kinetochore:Mad1:MAD2 ComplexComplexR-HSA-141427 (Reactome) Mad2 binds to the Mad1:Kinetochore and undergoes a major conformational change within the complex to assume the form Mad2*.
Kinetochore:Mad1:MAD2* ComplexComplexR-HSA-141432 (Reactome)
KinetochoreComplexR-HSA-375305 (Reactome)
MAD1L1 ProteinQ9Y6D9 (Uniprot-TrEMBL)
MAD1L1ProteinQ9Y6D9 (Uniprot-TrEMBL)
MAD2*CDC20 complexComplexR-HSA-141408 (Reactome) Activated Mad2 upon release from kinetochores binds and sequesters Cdc20 from activating the APC.
MAD2L1 ProteinQ13257 (Uniprot-TrEMBL)
MAD2L1ProteinQ13257 (Uniprot-TrEMBL)
MAPRE1 ProteinQ15691 (Uniprot-TrEMBL)
MCC:APC/C complexComplexR-HSA-141410 (Reactome)
MCM10 ProteinQ7L590 (Uniprot-TrEMBL)
MCM2 ProteinP49736 (Uniprot-TrEMBL)
MCM3 ProteinP25205 (Uniprot-TrEMBL)
MCM4 ProteinP33991 (Uniprot-TrEMBL)
MCM5 ProteinP33992 (Uniprot-TrEMBL)
MCM6 ProteinQ14566 (Uniprot-TrEMBL)
MCM7 ProteinP33993 (Uniprot-TrEMBL)
MCM8 ProteinQ9UJA3 (Uniprot-TrEMBL)
MDM4 ProteinO15151 (Uniprot-TrEMBL)
MIS12 ProteinQ9H081 (Uniprot-TrEMBL)
MLF1IP ProteinQ71F23 (Uniprot-TrEMBL)
MRE11A ProteinP49959 (Uniprot-TrEMBL)
Mad1:kinetochore complexComplexR-HSA-141441 (Reactome) The molecules that directly interact with Mad1 is unknown. However molecular genetic data has defined an assembly pathway consisting of CENP-I, HEC1, Mps1 that specifies the assembly of Mad1.
Me2K21-HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
NDC80 ProteinO14777 (Uniprot-TrEMBL)
NDE1 ProteinQ9NXR1 (Uniprot-TrEMBL)
NDEL1 ProteinQ9GZM8 (Uniprot-TrEMBL)
NSL1 ProteinQ96IY1 (Uniprot-TrEMBL)
NUDC ProteinQ9Y266 (Uniprot-TrEMBL)
NUF2 ProteinQ9BZD4 (Uniprot-TrEMBL)
NUP107 ProteinP57740 (Uniprot-TrEMBL)
NUP133 ProteinQ8WUM0 (Uniprot-TrEMBL)
NUP160 ProteinQ12769 (Uniprot-TrEMBL)
NUP37 ProteinQ8NFH4 (Uniprot-TrEMBL)
NUP43 ProteinQ8NFH3 (Uniprot-TrEMBL)
NUP85 ProteinQ9BW27 (Uniprot-TrEMBL)
NUP98-5 ProteinP52948-5 (Uniprot-TrEMBL)
ORC1 ProteinQ13415 (Uniprot-TrEMBL)
ORC2 ProteinQ13416 (Uniprot-TrEMBL)
ORC3 ProteinQ9UBD5 (Uniprot-TrEMBL)
ORC4 ProteinO43929 (Uniprot-TrEMBL)
ORC5 ProteinO43913 (Uniprot-TrEMBL)
ORC6 ProteinQ9Y5N6 (Uniprot-TrEMBL)
PAFAH1B1 ProteinP43034 (Uniprot-TrEMBL)
PCBP4 ProteinP57723 (Uniprot-TrEMBL)
PCBP4:CDKN1A mRNAComplexR-HSA-6803405 (Reactome)
PCBP4ProteinP57723 (Uniprot-TrEMBL)
PHF20ProteinQ9BVI0 (Uniprot-TrEMBL)
PIAS4 ProteinQ8N2W9 (Uniprot-TrEMBL)
PKMYT1ProteinQ99640 (Uniprot-TrEMBL)
PLK1 ProteinP53350 (Uniprot-TrEMBL)
PMF1 ProteinQ6P1K2 (Uniprot-TrEMBL)
PPP1CC ProteinP36873 (Uniprot-TrEMBL)
PPP2CA ProteinP67775 (Uniprot-TrEMBL)
PPP2CB ProteinP62714 (Uniprot-TrEMBL)
PPP2R1A ProteinP30153 (Uniprot-TrEMBL)
PPP2R1B ProteinP30154 (Uniprot-TrEMBL)
PPP2R5A ProteinQ15172 (Uniprot-TrEMBL)
PPP2R5B ProteinQ15173 (Uniprot-TrEMBL)
PPP2R5C ProteinQ13362 (Uniprot-TrEMBL)
PPP2R5D ProteinQ14738 (Uniprot-TrEMBL)
PPP2R5E ProteinQ16537 (Uniprot-TrEMBL)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7 ProteinO14818 (Uniprot-TrEMBL)
PSMA8 ProteinQ8TAA3 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB11 ProteinA5LHX3 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1 ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6 ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4 ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6 ProteinQ15008 (Uniprot-TrEMBL)
PSMD7 ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSME4 ProteinQ14997 (Uniprot-TrEMBL)
PSMF1 ProteinQ92530 (Uniprot-TrEMBL)
Persistent single-stranded DNAR-NUL-176104 (Reactome)
Persistent single-stranded DNA R-NUL-176104 (Reactome)
PolyUb,p-S166,S188-MDM2 ProteinQ00987 (Uniprot-TrEMBL)
PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4ComplexR-HSA-6804937 (Reactome)
PolyUb,p-S342,S367,S403-MDM4 ProteinO15151 (Uniprot-TrEMBL)
PolyUb-TP53 ProteinP04637 (Uniprot-TrEMBL)
PolyUb-TP53 TetramerComplexR-HSA-3209186 (Reactome)
PolyUb-TP53 TetramerComplexR-HSA-8856287 (Reactome)
RAD1 ProteinO60671 (Uniprot-TrEMBL)
RAD17 ProteinO75943 (Uniprot-TrEMBL)
RAD17:RFCComplexR-HSA-176353 (Reactome) The Rad17-RFC complex is a heteropentamer structurally similar to RFC. The Rad17-RFC complex contains the four smaller RFC subunits (Rfc2 [p37], Rfc3 [p36], Rfc4 [p40], and Rfc5 [p38]) and the 75 kDa Rad17 subunit in place of the Rfc1 [p140] subunit. The Rad17 complex contains a weak ATPase that is poorly stimulated by primed DNA. Along with binding the 9-1-1 complex and RPA, the Rad17-RFC complex interacts with human MCM7 protein. Each of these interactions is critical for Chk1 activation.

The Rad17 subunit is conserved evolutionarily with the protein showing 49% identity at the amino acid level with the S. pombe rad17 protein. Targeted deletion of the N-terminal region of mouse Rad17 leads to embryonic lethality, strongly suggesting that human Rad17 is also essential for long-term viability.

RAD50 ProteinQ92878 (Uniprot-TrEMBL)
RAD9:HUS1:RAD1ComplexR-HSA-176312 (Reactome) The Rad9-Hus1-Rad1 (9-1-1) complex is a ring-shaped heterotrimeric complex. Under genotoxic stress conditions, it can be loaded onto DNA at sites of damage or stalled forks by the Rad17 complex.
RAD9A ProteinQ99638 (Uniprot-TrEMBL)
RAD9B ProteinQ6WBX8 (Uniprot-TrEMBL)
RANBP2 ProteinP49792 (Uniprot-TrEMBL)
RANGAP1 ProteinP46060 (Uniprot-TrEMBL)
RCC2 ProteinQ9P258 (Uniprot-TrEMBL)
RFC2 ProteinP35250 (Uniprot-TrEMBL)
RFC3 ProteinP40938 (Uniprot-TrEMBL)
RFC4 ProteinP35249 (Uniprot-TrEMBL)
RFC5 ProteinP40937 (Uniprot-TrEMBL)
RFWD2ProteinQ8NHY2 (Uniprot-TrEMBL)
RHNO1 ProteinQ9BSD3 (Uniprot-TrEMBL)
RMI1 ProteinQ9H9A7 (Uniprot-TrEMBL)
RMI2 ProteinQ96E14 (Uniprot-TrEMBL)
RNF168 ProteinQ8IYW5 (Uniprot-TrEMBL)
RNF8 ProteinO76064 (Uniprot-TrEMBL)
RPA complexed to ssDNAComplexR-HSA-176293 (Reactome) RPA associates with ssDNA in distinct complexes that can be distinguished by the length of ssDNA occluded by each RPA molecule. These complexes reflect the progressive association of distinct DNA-binding domains present in the RPA heterotrimeric structure. Binding is coupled to significant conformational changes within RPA that are observable at the microscopic level. Presumably, the different conformations of free and ssDNA-bound RPA allow the protein to selectively interact with factors such as ATR-ATRIP when bound to DNA.
RPA heterotrimerComplexR-HSA-68462 (Reactome)
RPA1 ProteinP27694 (Uniprot-TrEMBL)
RPA2 ProteinP15927 (Uniprot-TrEMBL)
RPA3 ProteinP35244 (Uniprot-TrEMBL)
RPS27 ProteinP42677 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
Rad17-RFC complex bound to DNAComplexR-HSA-176204 (Reactome) Rad17-RFC complex associates with DNA substrates containing ssDNA regions including gapped or primed DNA in an ATP-independent reaction. Loading of the Rad9-Hus1-Rad1 (9-1-1) complex occurs preferentially on DNA substrates containing a 5' recessed end. This contrasts with the loading of PCNA by RFC which preferentially occurs on DNA with 3' recessed ends.
Rad9-Hus1-Rad1 bound to DNAComplexR-HSA-176256 (Reactome) A major known function of the 9-1-1 complex is to recruit Chk1 to stalled replication forks for activation by ATR. However, the presence of the 9-1-1 complex also alters the ability of Rad17 to become phoshorylated, perhaps suggesting that 9-1-1 may also serve to recruit a subset of ATR substrates. The 9-1-1 complex has also been found to interact with base excision repair factors human DNA polymerase beta, flap endonuclease FEN1, and the S. pombe MutY homolog (SpMYH), indicating that 9-1-1 also plays a direct role in DNA repair.
SEC13 ProteinP55735 (Uniprot-TrEMBL)
SEH1L-1 ProteinQ96EE3-1 (Uniprot-TrEMBL)
SFN ProteinP31947 (Uniprot-TrEMBL)
SGOL1 ProteinQ5FBB7 (Uniprot-TrEMBL)
SGOL2 ProteinQ562F6 (Uniprot-TrEMBL)
SHFM1 ProteinP60896 (Uniprot-TrEMBL)
SKA1 ProteinQ96BD8 (Uniprot-TrEMBL)
SKA2 ProteinQ8WVK7 (Uniprot-TrEMBL)
SPC24 ProteinQ8NBT2 (Uniprot-TrEMBL)
SPC25 ProteinQ9HBM1 (Uniprot-TrEMBL)
SPDL1 ProteinQ96EA4 (Uniprot-TrEMBL)
TAOK1 ProteinQ7L7X3 (Uniprot-TrEMBL)
TOP3A ProteinQ13472 (Uniprot-TrEMBL)
TOPBP1 ProteinQ92547 (Uniprot-TrEMBL)
TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 TetramerComplexR-HSA-3209194 (Reactome)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UBE2C ProteinO00762 (Uniprot-TrEMBL)
UBE2D1 ProteinP51668 (Uniprot-TrEMBL)
UBE2E1 ProteinP51965 (Uniprot-TrEMBL)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2V2 ProteinQ15819 (Uniprot-TrEMBL)
UIMC1 ProteinQ96RL1 (Uniprot-TrEMBL)
Ub-p-S123-CDC25AComplexR-HSA-69589 (Reactome) A number of ubiquitin moeities are covalently added to the Cdc25A, which marks it for proteolytic degradation.
UbComplexR-HSA-113595 (Reactome)
UbComplexR-HSA-68524 (Reactome)
Ubiquitin ligaseR-HSA-69593 (Reactome)
WEE1ProteinP30291 (Uniprot-TrEMBL)
WRN ProteinQ14191 (Uniprot-TrEMBL)
XPO1 ProteinO14980 (Uniprot-TrEMBL)
YWHAB ProteinP31946 (Uniprot-TrEMBL)
YWHAE ProteinP62258 (Uniprot-TrEMBL)
YWHAG ProteinP61981 (Uniprot-TrEMBL)
YWHAH ProteinQ04917 (Uniprot-TrEMBL)
YWHAQ ProteinP27348 (Uniprot-TrEMBL)
YWHAZ ProteinP63104 (Uniprot-TrEMBL)
ZNF385A ProteinQ96PM9 (Uniprot-TrEMBL)
ZNF385AProteinQ96PM9 (Uniprot-TrEMBL)
ZW10 ProteinO43264 (Uniprot-TrEMBL)
ZWILCH ProteinQ9H900 (Uniprot-TrEMBL)
ZWINT ProteinO95229 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
cyclin R-HSA-68379 (Reactome)
hBUBR1:hBUB3:MAD2*:CDC20 complexComplexR-HSA-141440 (Reactome)
origin of replication R-NUL-68419 (Reactome)
p-5S,T-MDM2ProteinQ00987 (Uniprot-TrEMBL)
p-5T-MDC1 ProteinQ14676 (Uniprot-TrEMBL)
p-S,3T-CHEK2ProteinO96017 (Uniprot-TrEMBL)
p-S102-WHSC1 ProteinO96028 (Uniprot-TrEMBL)
p-S123-CDC25A ProteinP30304 (Uniprot-TrEMBL)
p-S123-CDC25AProteinP30304 (Uniprot-TrEMBL)
p-S1387,S1423,S1524,S1547-BRCA1 ProteinP38398 (Uniprot-TrEMBL)
p-S15,S20-TP53 Tetramer:ZNF385A:CDKN1A GeneComplexR-HSA-6803802 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385AComplexR-HSA-6803718 (Reactome)
p-S15,S20-TP53 TetramerComplexR-HSA-3222171 (Reactome)
p-S15,S20-TP53 ProteinP04637 (Uniprot-TrEMBL)
p-S15-TP53 ProteinP04637 (Uniprot-TrEMBL)
p-S15-TP53 TetramerComplexR-HSA-349474 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2,MDM4:TP53
ComplexR-HSA-6804885 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2:MDM4
ComplexR-HSA-6804745 (Reactome)
p-S166,S188-MDM2 ProteinQ00987 (Uniprot-TrEMBL)
p-S166,S188-MDM2,MDM4ComplexR-HSA-6804750 (Reactome)
p-S166,S188-MDM2:MDM4ComplexR-HSA-6804932 (Reactome)
p-S166,S188-MDM2:p-S346,S367,S403-MDM4ComplexR-HSA-6804936 (Reactome)
p-S166,S188-MDM2:p-S403-MDM4ComplexR-HSA-6804939 (Reactome)
p-S166,S188-MDM2ProteinQ00987 (Uniprot-TrEMBL)
p-S1981,Ac-K3016-ATM ProteinQ13315 (Uniprot-TrEMBL)
p-S1981,Ac-K3016-ATMProteinQ13315 (Uniprot-TrEMBL)
p-S216-CDC25C ProteinP30307 (Uniprot-TrEMBL)
p-S216-CDC25C:14-3-3 protein complexComplexR-HSA-75005 (Reactome)
p-S216-CDC25CProteinP30307 (Uniprot-TrEMBL)
p-S25,S1778-TP53BP1 ProteinQ12888 (Uniprot-TrEMBL)
p-S317,S345-CHEK1ProteinO14757 (Uniprot-TrEMBL)
p-S327,T847,T859-RBBP8 ProteinQ99708 (Uniprot-TrEMBL)
p-S343-NBN ProteinO60934 (Uniprot-TrEMBL)
p-S346,S367,S403-MDM4 ProteinO15151 (Uniprot-TrEMBL)
p-S387-RFWD2 ProteinQ8NHY2 (Uniprot-TrEMBL)
p-S387-RFWD2:p-S15-TP53ComplexR-HSA-349420 (Reactome)
p-S387-RFWD2ProteinQ8NHY2 (Uniprot-TrEMBL)
p-S403-MDM4 ProteinO15151 (Uniprot-TrEMBL)
p-S406-FAM175A ProteinQ6UWZ7 (Uniprot-TrEMBL)
p-S435-GTSE1 ProteinQ9NYZ3 (Uniprot-TrEMBL)
p-S435-GTSE1:PolyUb-TP53 TetramerComplexR-HSA-8852344 (Reactome)
p-S435-GTSE1:PolyUb-TP53 TetramerComplexR-HSA-8852349 (Reactome)
p-S435-GTSE1ProteinQ9NYZ3 (Uniprot-TrEMBL)
p-S988,S1387,S1423,S1524,S1547-BRCA1 ProteinP38398 (Uniprot-TrEMBL)
p-S990,Ac-K1249-BRIP1 ProteinQ9BX63 (Uniprot-TrEMBL)
p-T14,T161-CDK1 ProteinP06493 (Uniprot-TrEMBL)
p-T14,Y15,T161-CDK1 ProteinP06493 (Uniprot-TrEMBL)
p-T14-CDK1 ProteinP06493 (Uniprot-TrEMBL)
p-T4827,SUMO1-HERC2 ProteinO95714 (Uniprot-TrEMBL)
p-T68-CHEK2 ProteinO96017 (Uniprot-TrEMBL)
p-T68-CHEK2 dimerComplexR-HSA-5683773 (Reactome)
p-T68-CHEK2ProteinO96017 (Uniprot-TrEMBL)
p-T714,T734-BARD1 ProteinQ99728 (Uniprot-TrEMBL)
p-T916,S945-CLSPN ProteinQ9HAW4 (Uniprot-TrEMBL)
p-WEE1ProteinP30291 (Uniprot-TrEMBL)
p14-ARF ProteinQ8N726 (Uniprot-TrEMBL)
p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4ComplexR-HSA-6804995 (Reactome)
phosphorylated

anaphase promoting

complex (APC/C)
ComplexR-HSA-174191 (Reactome)
ubiquitinated phospho-COP1(ser-387)ComplexR-HSA-349433 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
14-3-3 dimerR-HSA-75016 (Reactome)
26S proteasomemim-catalysisR-HSA-264458 (Reactome)
26S proteasomemim-catalysisR-HSA-69600 (Reactome)
26S proteasomemim-catalysisR-HSA-8852354 (Reactome)
ADPArrowR-HSA-170055 (Reactome)
ADPArrowR-HSA-170070 (Reactome)
ADPArrowR-HSA-176116 (Reactome)
ADPArrowR-HSA-176298 (Reactome)
ADPArrowR-HSA-349426 (Reactome)
ADPArrowR-HSA-349444 (Reactome)
ADPArrowR-HSA-349455 (Reactome)
ADPArrowR-HSA-5683792 (Reactome)
ADPArrowR-HSA-5693609 (Reactome)
ADPArrowR-HSA-6799246 (Reactome)
ADPArrowR-HSA-6799332 (Reactome)
ADPArrowR-HSA-6804955 (Reactome)
ADPArrowR-HSA-69604 (Reactome)
ADPArrowR-HSA-69608 (Reactome)
ADPArrowR-HSA-69685 (Reactome)
ADPArrowR-HSA-69889 (Reactome)
ADPArrowR-HSA-69891 (Reactome)
ADPArrowR-HSA-75010 (Reactome)
ADPArrowR-HSA-75028 (Reactome)
ADPArrowR-HSA-75809 (Reactome)
ATPR-HSA-170055 (Reactome)
ATPR-HSA-170070 (Reactome)
ATPR-HSA-176116 (Reactome)
ATPR-HSA-176298 (Reactome)
ATPR-HSA-349426 (Reactome)
ATPR-HSA-349444 (Reactome)
ATPR-HSA-349455 (Reactome)
ATPR-HSA-5683792 (Reactome)
ATPR-HSA-5693609 (Reactome)
ATPR-HSA-6799246 (Reactome)
ATPR-HSA-6799332 (Reactome)
ATPR-HSA-6804955 (Reactome)
ATPR-HSA-69604 (Reactome)
ATPR-HSA-69608 (Reactome)
ATPR-HSA-69685 (Reactome)
ATPR-HSA-69889 (Reactome)
ATPR-HSA-69891 (Reactome)
ATPR-HSA-75010 (Reactome)
ATPR-HSA-75028 (Reactome)
ATPR-HSA-75809 (Reactome)
ATR:ATRIP:RPA:3'

overhanging

ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:RAD17:RFC:RAD9:HUS1:RAD1:RHNO1:TOPBP1
mim-catalysisR-HSA-6799332 (Reactome)
ATR:ATRIP:RPA:ssDNA signaling complexArrowR-HSA-176250 (Reactome)
ATR:ATRIPR-HSA-176250 (Reactome)
ATR:ATRIPmim-catalysisR-HSA-176116 (Reactome)
ATR:ATRIPmim-catalysisR-HSA-176298 (Reactome)
Activated MAD2L1ArrowR-HSA-141439 (Reactome)
Activated MAD2L1R-HSA-141429 (Reactome)
Activated MAD2L1R-HSA-141437 (Reactome)
BUB1BR-HSA-141437 (Reactome)
BUB3R-HSA-141437 (Reactome)
CCNA:CDK2R-HSA-187934 (Reactome)
CCNB1:p-T14,T161-CDK1R-HSA-170070 (Reactome)
CCNB1:p-T14,Y15,T161-CDK1ArrowR-HSA-170070 (Reactome)
CCNB:CDK1R-HSA-170055 (Reactome)
CCNB:p-T14-CDK1ArrowR-HSA-170055 (Reactome)
CCNE:CDK2R-HSA-69562 (Reactome)
CDC20R-HSA-141429 (Reactome)
CDC20R-HSA-141437 (Reactome)
CDC25AR-HSA-69604 (Reactome)
CDC25AR-HSA-69608 (Reactome)
CDC25CR-HSA-75010 (Reactome)
CDC25CR-HSA-75809 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45
R-HSA-176318 (Reactome)
CDKN1A geneR-HSA-6803388 (Reactome)
CDKN1A geneR-HSA-6803801 (Reactome)
CDKN1A mRNAArrowR-HSA-6803388 (Reactome)
CDKN1A mRNAR-HSA-6803403 (Reactome)
CDKN1A mRNAR-HSA-6803411 (Reactome)
CDKN1A,CDKN1BR-HSA-187934 (Reactome)
CDKN1A,CDKN1BR-HSA-69562 (Reactome)
CDKN1A,CDKN1Bmim-catalysisR-HSA-187934 (Reactome)
CDKN1A,CDKN1Bmim-catalysisR-HSA-69562 (Reactome)
CDKN1AArrowR-HSA-6803411 (Reactome)
CHEK1R-HSA-176116 (Reactome)
CHEK1R-HSA-69889 (Reactome)
CHEK2R-HSA-5683735 (Reactome)
CLSPNR-HSA-176318 (Reactome)
Cdc45:CDK:DDK:Mcm10:Activated claspin:pre-replicative complexArrowR-HSA-176298 (Reactome)
Cdc45:CDK:DDK:Mcm10:claspin:pre-replicative complexArrowR-HSA-176318 (Reactome)
Cdc45:CDK:DDK:Mcm10:claspin:pre-replicative complexR-HSA-176298 (Reactome)
Cyclin

A:Cdk2:p21/p27

complex
ArrowR-HSA-187934 (Reactome)
Cyclin E:CDK2:CDKN1A,CDKN1BArrowR-HSA-69562 (Reactome)
DNA

DNA

DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex:CHEK2
ArrowR-HSA-5683735 (Reactome)
DNA

DNA

DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex:CHEK2
R-HSA-69891 (Reactome)
DNA

DNA

DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex:CHEK2
mim-catalysisR-HSA-69891 (Reactome)
DNA

DNA

DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex
ArrowR-HSA-69891 (Reactome)
DNA

DNA

DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex
R-HSA-5683735 (Reactome)
Kinetochore:Mad1:MAD2 ComplexArrowR-HSA-141431 (Reactome)
Kinetochore:Mad1:MAD2 ComplexR-HSA-141422 (Reactome)
Kinetochore:Mad1:MAD2* ComplexArrowR-HSA-141422 (Reactome)
Kinetochore:Mad1:MAD2* ComplexR-HSA-141439 (Reactome)
KinetochoreR-HSA-141409 (Reactome)
MAD1L1R-HSA-141409 (Reactome)
MAD2*CDC20 complexArrowR-HSA-141429 (Reactome)
MAD2L1R-HSA-141431 (Reactome)
MCC:APC/C complexArrowR-HSA-141423 (Reactome)
Mad1:kinetochore complexArrowR-HSA-141409 (Reactome)
Mad1:kinetochore complexArrowR-HSA-141439 (Reactome)
Mad1:kinetochore complexR-HSA-141431 (Reactome)
PCBP4:CDKN1A mRNAArrowR-HSA-6803403 (Reactome)
PCBP4:CDKN1A mRNATBarR-HSA-6803411 (Reactome)
PCBP4R-HSA-6803403 (Reactome)
PHF20TBarR-HSA-5633460 (Reactome)
PKMYT1mim-catalysisR-HSA-170055 (Reactome)
Persistent single-stranded DNAR-HSA-176175 (Reactome)
PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4ArrowR-HSA-6804724 (Reactome)
PolyUb-TP53 TetramerArrowR-HSA-6793685 (Reactome)
PolyUb-TP53 TetramerArrowR-HSA-6804879 (Reactome)
PolyUb-TP53 TetramerR-HSA-6793685 (Reactome)
PolyUb-TP53 TetramerR-HSA-8852337 (Reactome)
R-HSA-141409 (Reactome) The association of Mad1 with the kinetochore is the first step in the process of Mad2 mediated amplification of the signal from defective kinetochores.
R-HSA-141422 (Reactome) In vitro structural studies have shown that Mad2 undergoes a major conformational change upon binding to Mad1. This conformational change is postulated to activate Mad2 into a high affinity state which can bind and sequester Cdc20 from the APC.
R-HSA-141423 (Reactome) In the direct inhibition model, association of the MCC with APCC results in the inactivation of APC/C. However, the affinity between MCC and APC/C is not high, so that the inhibition is readily reversible. The role of unattached kinetochores is to sensitize the APC/C to prolonged inhibition by the MCC.
R-HSA-141429 (Reactome) In the sequestration model, the Mad2 molecules that dissociate from unattached kinetochores are perceived to bind to Cdc20, a protein that recruits specific substrates to the APC/C. Consequently, Mad2 indirectly inhibits the APC/C by sequestering its activator, Cdc20. This requires interaction between Mad1 and Mad2. Cdc20 and Mad1 bind to the same site on Mad2.
R-HSA-141431 (Reactome) Mad2 is recruited to the kinetochore through an interaction with Mad1.
R-HSA-141437 (Reactome) Upon release from the kinetochore, Mad2 associates with Cdc20, hBUBR1, and hBUB3 to form the Mitotic Checkpoint Complex (MCC). Assembly of this complex does not depend on kinetochores but this complex can only inhibit APC/C that has undergone mitotic modifications.
R-HSA-141439 (Reactome) The mechanism by which the conformationally altered inhibitory form of Mad2 is released from its association with Mad1 at the kinetochore is not known. Mad1 and Cdc20 have a common 10 residue Mad2 binding motif. Therefore, one possibility is that Mad2 is transferred competitively from Mad1 to Cdc20 (Luo et al., 2002; Sironi et al., 2002).
R-HSA-170055 (Reactome) Myt1, which localizes preferentially to the endoplasmic reticulum and Golgi complex, phosphorylates Cdc2 on threonine 14 ( Liu et al., 1997).
R-HSA-170070 (Reactome) WEE1, a nuclear kinase, phosphorylates cyclin B1:Cdc2 (CCNB1:CDK1) on tyrosine 15 (Y15), inactivating the complex (Parker and Piwnica-Worms 1992, McGowan and Russell 1993). The complex of cyclin B2 and Cdc2 (CCNB2:CDK1) is also phosphorylated on Y15 (Galaktionov and Beach 1991).
R-HSA-176101 (Reactome) The Rad17-RFC complex is involved in an early stage of the genotoxic stress response. The major function of the protein complex is to load the Rad9-Hus1-Rad1 (9-1-1) complex onto DNA at sites of damage and/or stalled replication forks. This reaction is conceptually similar to the loading of the PCNA sliding clamp onto DNA by RFC. The association of the Rad17-RFC complex with ssDNA or gapped or primed DNA is significantly stimulated by RPA, but not by the heterologous E. coli SSB. Loading of the human 9-1-1 complex onto such DNA templates is also strongly stimulated by cognate RPA, but not yeast RPA. Although Rad17 and Rad9 are substrates of the ATR kinase activity, loading of the Rad17 and 9-1-1 complexes onto DNA occurs independent of ATR.

The Rad17-RFC complex is a heteropentamer structurally similar to RFC. The complex contains the four smaller RFC subunits (Rfc2 [p37], Rfc3 [p36], Rfc4 [p40], and Rfc5 [p38]) and the 75 kDa Rad17 subunit in place of the Rfc1 [p140] subunit. The Rad17 complex contains a weak ATPase that is slightly stimulated by primed DNA. Along with binding the 9-1-1 complex and RPA, the Rad17-RFC complex interacts with human MCM7 protein. Each of these interactions is critical for Chk1 activation.

The Rad17 subunit is conserved evolutionarily with the protein showing 49% identity at the amino acid level with the S. pombe rad17 protein. Targeted deletion of the N-terminal region of mouse Rad17 leads to embryonic lethality, strongly suggesting that human Rad17 is also essential for long-term viability.

Rad17-RFC complex associates with DNA substrates containing ssDNA regions including gapped or primed DNA in an ATP-independent reaction. Loading of the Rad9-Hus1-Rad1 (9-1-1) complex occurs preferentially on DNA substrates containing a 5' recessed end. This contrasts with the loading of PCNA by RFC which preferentially occurs on DNA with 3' recessed ends.

R-HSA-176116 (Reactome) Chk1 is a checkpoint kinase activated during genotoxic stress. Like ATR, Chk1 is essential for viability in mammals. Targeted gene disruption in mice shows that loss of Chk1 causes peri-implantation embryonic lethality. Even though ATR-ATRIP not bound to ssDNA can phosphorylate Chk1, Chk1 activation is greatly enhanced when recruited to stalled replication forks by physical interaction with a modified form of claspin and the Rad9-Hus1-Rad1 sliding clamp. Activation of Chk1 occurs following phosphorylation of two sites (serine 317 and serine 345). Mutational analysis indicates that modification of both sites is essential for maximal kinase activity, while phosphorylation of only a single site causes only weak activation of Chk1. Following phosphorylation, Chk1 can diffuse away from the complex to further amplify the checkpoint signal. ATR appears to be the primary kinase activating Chk1 as conditions that activate ATR (ultraviolet irradiation or treatment with hydroxyurea) also activate Chk1. Stresses that activate ATM, e.g., ionizing irradiation, do not cause significant Chk1 activation. While the ATR and ATM pathways are distinct, there is interplay between the two. For example, double-strand DNA breaks can be processed in an ATM-dependent manner to generate structures that can cause ATR and hence Chk1 activation. The ATR and ATM pathways also have mechanistic similarities. Analogous to the Chk1 kinase existing downstream of ATR, the Chk2 checkpoint kinase is modified and activated by ATM. Although having distinct structures, Chk1 and Chk2 also have overlapping targets with some substrate sites phosphorylatable by both kinases (e.g., serine 20 of p53).
R-HSA-176175 (Reactome) When a DNA replication fork encounters DNA lesions (e.g., cyclobutane pyrimidine dimers or alkylated bases) stalling of the replicative DNA polymerase may occur. This can lead to dissociation or 'uncoupling' of the DNA polymerase from the DNA helicase and generation of long regions of persistent ssDNA. Uncoupling can also occur in response to other genotoxic stresses such as reduced dNTP pools caused by hydroxyurea treatment which inhibits cellular ribonucleotide diphosphate reductase. The exposed ssDNA is bound by the single-stranded DNA binding protein RPA. The persistent nature of this RPA-ssDNA complex (as opposed to a more-transient complex found at an active replication fork) allows it to serve as a signal for replication stress that can be recognized by the ATR-ATRIP and Rad17-Rfc2-5 complexes.

RPA associates with ssDNA in distinct complexes that can be distinguished by the length of ssDNA occluded by each RPA molecule. These complexes reflect the progressive association of distinct DNA-binding domains present in the RPA heterotrimeric structure. Binding is coupled to significant conformational changes within RPA that are observable at the microscopic level. Presumably, the different conformations of free and ssDNA-bound RPA allow the protein to selectively interact with factors such as ATR-ATRIP when bound to DNA.

R-HSA-176250 (Reactome) ATR kinase activity is stimulated upon binding of the ATR-ATRIP complex to an RPA-ssDNA complex. ATR can subsequently phosphorylate and activate the checkpoint kinase Chk1, allowing further amplification of the checkpoint signal. The ATR and Chk1 kinases then modify a variety of factors that can lead to stabilization of stalled DNA replication forks, inhibition of origin firing, inhibition of cell cycle progression, mobilization of DNA repair factors, and induction of apoptosis. This checkpoint signaling mechanism is highly conserved in eukaryotes, and homologues of ATR and ATRIP are found in such organisms as S. cerevisiae (Mec1 and Ddc2, respectively), S. pombe (rad3 and rad26, respectively), and X. laevis (Xatr and Xatrip, respectively).

The ATR (ATM- and rad3-related) kinase is an essential checkpoint factor in human cells. In response to replication stress (i.e., stresses that cause replication fork stalling) or ultraviolet radiation, ATR becomes active and phosphorylates numerous factors involved in the checkpoint response including the checkpoint kinase Chk1. ATR is invariably associated with ATRIP (ATR-interacting protein) in human cells. Depletion of ATRIP by siRNA causes a loss of ATR protein without affecting ATR mRNA levels indicating that complex formation stabilizes the ATR protein. ATRIP is also a substrate for the ATR kinase, but modification of ATRIP does not significantly regulate the recruitment of ATR-ATRIP to sites of damage, the activation of Chk1, or the modification of p53.

While the ATR-ATRIP complex binds only poorly to RPA complexed with ssDNA lengths of 30 or 50 nt, binding is significantly enhanced in the presence of a 75 nt ssDNA molecule. Complex formation is primarily mediated by physical interaction between ATRIP and RPA. Multiple elements within the ATRIP molecule can bind to the RPA-ssDNA complex, including residues 1-107 (highest affinity), 218-390, and 390-791 (lowest affinity). Although the full-length ATRIP is unable to bind ssDNA, an internal region (108-390) can weakly bind ssDNA when present in rabbit reticulocyte lysates. ATR can bind to the ssDNA directly independent of RPA, but this binding is inhibited by ATRIP. Upon binding, the ATR kinase becomes activated and can directly phosphorylate substrates such as Rad17.

R-HSA-176264 (Reactome) The 9-1-1 complex is a heterotrimeric ring-shaped structure that is loaded onto DNA by the Rad17-RFC complex. In vitro studies indicate that loading is preferred onto DNA substrates containing ssDNA gaps that presumably resemble structures found upon replication fork stalling and DNA polymerase/helicase uncoupling. The Rad17-RFC and 9-1-1 complexes are structurally similar to the RFC (replication factor C) clamp loader and PCNA sliding clamp, respectively, and similar mechanisms are thought to be used during loading of the 9-1-1 complex and PCNA. Upon loading, the 9-1-1 complex can recruit Chk1 onto sites of replication fork uncoupling or DNA damage.

The purified Rad17 and Rad9-Hus1-Rad1 (9-1-1) complexes can form a stable co-complex in the presence of ATP, using Rad17-Rad9 interactions. From computer modeling studies, the Rad17 subunit of the complex is also proposed to interact with the C-terminus of Rad1, p36 with the C-terminus of Hus1, and p38 with the C-terminus of Rad9. A major known function of the 9-1-1 complex is to recruit Chk1 to stalled replication forks for activation by ATR. However, the presence of the 9-1-1 complex also alters the ability of Rad17 to become phosphorylated, perhaps suggesting that 9-1-1 may regulate the recruiment of additional ATR substrates. The 9-1-1 complex has also been found to interact with base excision repair factors human DNA polymerase beta, flap endonuclease FEN1, and the S. pombe MutY homolog (SpMYH), indicating that 9-1-1 also plays a direct role in DNA repair.

R-HSA-176298 (Reactome) Claspin is a replication fork-associated protein important for Chk1 activation. Claspin loads onto the fork during replication origin firing and travels with the fork during DNA synthesis. Upon fork uncoupling and ATR-ATRIP binding to persistent ssDNA, the activated ATR kinase phosphorylates claspin at two primary sites. Modification increases the affinity of claspin for Chk1. Studies of human or Xenopus claspin indicate that phosphorylation of both sites is essential for significant claspin-Chk1 association. Following claspin modification by ATR, Chk1 can be transiently recruited to the stalled replication fork for subsequent phosphorylation and activation by ATR. Activation of Chk1 allows modification of additional downstream targets, thus amplifying the checkpoint signal. While much of the mechanistic information concerning claspin action has been obtained using Xenopus laevis egg extracts and Xenopus claspin, factors with similar activity have been found in various eukaryotic species including S. cerevisiae (MRC1), S. pombe (mrc1), and humans.

Activated ATR phosphorylates human claspin on two sites, threonine 916 and serine 945.

R-HSA-176318 (Reactome) Claspin is loaded onto DNA replication origins during replication initiation. Studies in Xenopus egg extracts indicate claspin loading requires the presence of Cdc45, a factor that promotes the initial unwinding of the origin DNA in the presence of Cdk2. This step is followed by RPA binding which is a prerequisite for recruitment of PCNA and DNA polymerases alpha and delta. As RPA is not required for claspin binding, it is postulated that claspin binds at the time of initial origin unwinding but prior to the initiation of DNA synthesis. Claspin would then continue to associate with replication fork machinery where it can serve as a checkpoint sensor protein. Even though associated with the replication fork, claspin is not an essential DNA replication factor.

Studies of Xenopus claspin indicate that it can physically associate with cognate Cdc45, DNA polymerase epsilon, RPA, RFC, and Rad17-RFC on chromatin. Studies of purified human claspin indicate that it binds with high affinity to branched (or forked) DNA structures that resemble stalled replication forks. Electron microscopy of these complexes indicates that claspin binds as a ring-like structure near the branch. The protein is hypothesized to encircle the DNA at these sites.

R-HSA-187934 (Reactome) During G1, the activity of cyclin-dependent kinases (CDKs) is controlled by the CDK inhibitors (CKIs) CDKN1A (p21) and CDKN1B (p27), thereby preventing premature entry into S phase (Guardavaccaro and Pagano, 2006).
R-HSA-264418 (Reactome) Ionizing radiation results in an ATM-dependent movement of COP1 from the nucleus to the cytoplasm (Dornan et al., 2006).
R-HSA-264435 (Reactome) ATM-dependent phosphorylation of COP1 on Ser(387) results in disruption of the COP1-p53 complex (Dornan et al., 2006)
R-HSA-264444 (Reactome) ATM phosphorylation promotes autoubiquitination of COP1 in vitro (Dornan et al., 2006). The number of ubiquitin molecules shown in this reaction is set arbitrarily at 4.
R-HSA-264458 (Reactome) Autoubiquitinated COP1 is degraded by the proteasome. The number of ubiquitin molecules shown in this reaction is arbitrarily set at 4. (Dornan et al., 2006).
R-HSA-349426 (Reactome) CHEK2 (Chk2) kinase is required for phosphorylation of MDM4 at serine residues S342 and S367 in vivo. CHEK2-mediated phosphorylation stimulates MDM4 ubiquitination by MDM2 and subsequent degradation (Chen et al. 2005).
R-HSA-349444 (Reactome) ATM phosphorylates COP1 on Ser387 in response to DNA damage (Dornan et al., 2006).
R-HSA-349455 (Reactome) Human MDM4 (MDMX) is phosphorylated on serine residue S403 by ATM. This site is important for MDM2-mediated ubiquitination of MDM4 after induction of double strand DNA breaks (Pereg et al. 2005, Chen et al. 2005).
R-HSA-5633460 (Reactome) The N-terminal portion of MDM2 binds the N-terminal transactivation domain of TP53 (p53) and inhibits transcriptional transactivation by TP53 (Momand et al. 1992, Oliner et al. 1992, Oliner et al. 1993, Chen et al. 1993).
R-HSA-5683735 (Reactome) CHEK2 (CHK2, Cds1) is recruited to DNA double strand breaks (DSBs) mainly through its interaction with TP53BP1 (53BP1) (Wang et al. 2002), but BRCA1 also contributes to CHEK2 recruitment (Wilson and Stern 2008).
R-HSA-5683774 (Reactome) ATM-mediated phosphorylation of CHEK2 (CHK2, Cds1) on threonine residue T68 promotes formation of transitional CHEK2 homodimers primarily through intermolecular interactions of FHA domains and phospho-T68 residues of two CHEK2 protomers (Cai et al. 2009).
R-HSA-5683792 (Reactome) Upon dimerization, p-T68-CHEK2 protomers trans-autophosphorylate on serine residue S379 (Lovly et al. 2008) and threonine residues T383 and T387 (Lee et al. 2001). Autophosphorylation leads to dissociation of CHEK2 dimers into active CHEK2 monomers (Cai et al. 2009).
R-HSA-5693609 (Reactome) In response to DNA double strand breaks, serine at position 15 of the TP53 (p53) tumor suppressor protein is rapidly phosphorylated by the ATM kinase. This serves to stabilize the p53 protein. A rise in the levels of the p53 protein induces the expression of p21 cyclin-dependent kinase inhibitor. This prevents the normal progression from G1 to S phase, thus providing a check on replication of damaged DNA (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998).
R-HSA-6793685 (Reactome) Upon MDM2-mediated ubiquitination, TP53 is exported from the nucleus to the cytosol. TP53 nuclear export requires the nuclear export sequence (NES) of TP53, but not the NES of MDM2 (Boyd et al. 2000. Geyer et al. 2000).
R-HSA-6799246 (Reactome) CHEK1, activated by ATR-mediated phosphorylation, can phosphorylate TP53 at serine residue S20, resulting in the increased half-life of TP53 (Shieh et al. 2000).
R-HSA-6799332 (Reactome) ATR, bound to DNA damage sites, phosphorylates TP53 (p53) at serine residue S15. S15 phosphorylation stabilizes TP53 by inhibiting the binding of TP53 to the ubiquitin ligase MDM2 (Tibbetts et al. 1999, Lakin et al. 1999).
R-HSA-6803388 (Reactome) Binding of TP53 (p53) to its response elements in the promoter of the CDKN1A (p21) gene stimulates CDKN1A transcription (El-Deiry et al. 1993). Binding of ZNF385A (HZF) to the DNA binding domain of TP53 facilitates CDKN1A induction and the consequent cell cycle arrest (Das et al. 2007).
R-HSA-6803403 (Reactome) PCBP4 binds the 3'-UTR of the CDKN1A (p21) mRNA and reduces its stability (Scoumanne et al. 2011).
R-HSA-6803411 (Reactome) PCBP4 binding to the 3'-UTR of the CDKN1A (p21) mRNA reduces half-life of the CDKN1A mRNA and the amount of CDKN1A protein. Upon DNA damage, TP53-mediated induction of CDKN1A is rapid, while the induction of PCBP4 is more gradual. It is hypothesized that, under prolonged stress, PCBP4-mediated down-regulation of CDKN1A may switch from G1 cell cycle arrest to G2 arrest, which may precede apoptosis (Scoumanne et al. 2011).
R-HSA-6803719 (Reactome) ZNF385A (HZF) forms a complex with TP53 (p53), interacting with the DNA binding domain of TP53. The complex of TP53 and ZNF385A associates with p53 response elements of cell cycle arrest genes, such as CDKN1A (p21) and stimulates their transcription. Under prolonged stress, ZNF385A undergoes ubiquitination and proteasome-mediated degradation, which coincides with expression of TP53-regulated pro-apoptotic genes (Das et al. 2007).
R-HSA-6803801 (Reactome) TP53 (p53) binds at least two p53 response elements in the promoter of the CDKN1A (p21, WAF1) gene (El-Deiry et al. 1993, Espinosa et al. 2003). Formation of the complex of TP53 and ZNF385A (HZF) facilitates binding of TP53 to the CDKN1A promoter (Das et al. 2007).
R-HSA-6804724 (Reactome) Once MDM4 is phosphorylated by ATM and CHEK2 in response to DNA damage, MDM2 ubiquitinates MDM4 and targets it for degradation (Chen et al. 2005, Pereg et al. 2005). The presence of MDM4 stimulates auto-ubiquitination of MDM2 (Linares et al. 2003).
R-HSA-6804741 (Reactome) To efficiently function as an E3 ubiquitin ligase, MDM2 has to form dimers or higher order oligomers. MDM2 can homodimerize (Cheng et al. 2011) or heterodimerize with MDM4 (MDMX) (Sharp et al. 1999, Huang et al. 2011, Pant et al. 2011). Dimerization involves the RING domain of MDM2 and/or MDM4. Heterodimers of MDM2 and MDM4 may be particularly important during embryonic development (Pant et al. 2011).
R-HSA-6804879 (Reactome) MDM2 is an ubiquitin ligase whose expression is positively regulated by TP53 (p53) (Wu et al. 1993). MDM2 binds TP53 tetramer (Maki 1999) and promotes its ubiquitination and subsequent degradation (Fuchs et al. 1998). Formation of MDM2 homodimers (Cheng et al. 2011) or heterodimers with MDM4 (MDMX) is needed for efficient ubiquitination of TP53 (Linares et al. 2003). While MDM2-TP53 binding occurs at the amino-terminus of TP53, MDM2 ubiquitinates TP53 lysine residues at the carboxy-terminus. Acetylation of those lysines can inhibit MDM2-dependent ubiquitination (Li et al. 2002).
R-HSA-6804955 (Reactome) ATM phosphorylates MDM2 on three serine residues (S386, S395, S407) and one threonine residue (T419) in vicinity to the RING domain. ATM-mediated phosphorylation of MDM2 in response to DNA damage (DNA double strand breaks) prevents MDM2 dimerization, binding of TP53 (p53) and MDM2-mediated ubiquitination of TP53 (Cheng et al. 2009, Cheng et al. 2011).
R-HSA-69562 (Reactome) During G1, the activity of cyclin-dependent kinases (CDKs) is controlled by the CDK inhibitors (CKIs) CDKN1A (p21) and CDKN1B (p27), thereby preventing premature entry into S phase (see Guardavaccaro and Pagano, 2006). The efficient recognition and ubiquitination of p27 by the SCF (Skp2) complex requires the formation of a trimeric complex containing p27 and cyclin E/A:Cdk2.
R-HSA-69598 (Reactome) At the beginning of this reaction, 1 molecule of 'ubiquitin', and 1 molecule of 'phospho-Cdc25A' are present. At the end of this reaction, 1 molecule of 'Ubiquitinated Phospho-Cdc25A' is present.

This reaction takes place in the 'cytosol' and is mediated by the 'ubiquitin-protein ligase activity' of 'Ubiquitin ligase' (Bernardi et al. 2000).

R-HSA-69600 (Reactome) At the beginning of this reaction, 1 molecule of 'Ubiquitinated Phospho-Cdc25A' is present. At the end of this reaction, 1 molecule of 'Amino Acid' is present.

This reaction takes place in the 'cytosol' and is mediated by the 'endopeptidase activity' of '26S proteasome' (Bernardi et al. 2000).

R-HSA-69604 (Reactome) Detection of DNA damage caused by ionizing radiation results in the phosphorylation of Cdc25A at Ser-123 by Chk1, inhibiting Cdc25A.
R-HSA-69608 (Reactome) Detection of DNA damage caused by ionizing radiation results in the phosphorylation of Cdc25A at Ser-123 by Chk2 (Mailand et al. 2001).
R-HSA-69685 (Reactome) CHEK2 (Chk2) phosphorylates TP53 (p53) at serine residue S20 (Hirao et al. 2000, Shieh et al. 2000, Chehab et al. 2000). Phosphorylation of TP53 at serine residue S20 is necessary for DNA damage-induced TP53 stabilization as it compromises the interaction of TP53 with the ubiquitin ligase MDM2 (Chehab et al. 1999, Chehab et al. 2000). S20 phosphorylation is also required for the induction of TP53-dependent transcripts in response to DNA damage (Hirao et al. 2000).
R-HSA-69889 (Reactome) At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'Chk1' are present. At the end of this reaction, 1 molecule of 'phospho-Chk1', and 1 molecule of 'ADP' are present.

This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'phospho-ATM (Ser 1981)'.

R-HSA-69891 (Reactome) Activated ATM phosphorylates CHEK2 (CHK2, Cds1) on threonine residue T68 (Matsuoka et al. 2000, Melchionna et al. 2000). The presence of BRCA1 and TP53BP1 positively regulates ATM-mediated phosphorylation of CHEK2 (Wang et al. 2002, Foray et al. 2003). ATM-mediated phosphorylation causes formation of CHEK2 dimers and dissociation of CHEK2 from chromatin (Li and Stern 2005).
R-HSA-75010 (Reactome) Phosphorylation of Cdc25C at Ser 216 results in both the inhibition of Cdc25C phosphatase activity and the creation of a 14-3-3 docking site (Peng et al. 1997).
R-HSA-75016 (Reactome) CDC25C is phosphorylated by CHK1 at ser-216 (Blasina et al.,1999 ) resulting in both inhibition of the CDC25 phosphatase activity and creation of a 14-3-3 docking site (Peng et al., 1997). Association of 14-3-3 proteins with phosphorylated CDC25C (p-S216-CDC25C) is thought to result in retention of this complex within the cytoplasm (Dalal et al., 1999; Graves et al, 2001).
R-HSA-75028 (Reactome) Phosphorylation of Wee1 by Chk1 stimulates Wee1 kinase activity.
R-HSA-75809 (Reactome) Cdc25C is negatively regulated by phosphorylation on Ser 216, the 14-3-3-binding site. This is an important regulatory mechanism used by cells to block mitotic entry under normal conditions and after DNA damage (Chaturvedi et al, 1999; Bulavin et al., 2003).
R-HSA-8852337 (Reactome) Since MDM2-mediated ubiquitination of TP53 promotes translocation of TP53 to the cytosol, and since GTSE1-facilitated translocation of TP53 to the cytosol depends on the functional MDM2 (with no reported interaction between GTSE1 and MDM2) (Monte et al. 2004), it is plausible that GTSE1 binds to TP53 polyubiquitinated by MDM2. The interaction between TP53 and GTSE1 involves the C-terminal regulatory domain of TP53 and the C-terminus of GTSE1 (Monte et al. 2003).
R-HSA-8852351 (Reactome) Binding of GTSE1 to TP53 (p53) in the nucleus promotes translocation of TP53 to the cytosol. This process is dependent on the nuclear export signal (NES) of GTSE1 (Monte et al. 2004).
R-HSA-8852354 (Reactome) GTSE1 promotes down-regulation of TP53 in a proteasome-dependent way. Nuclear export of TP53 facilitated by GTSE1 and MDM2likely makes ubiquitinated TP53 available to the proteasome machinery. GTSE1-mediated decrease of TP53 levels is needed for the G2 checkpoint recovery (cell cycle re-entry after DNA damage induced G2 arrest) and rescues cells from DNA damage induced apoptosis during S/G2 phase (Monte et al. 2003, Monte et al. 2004).
RAD17:RFCR-HSA-176101 (Reactome)
RAD9:HUS1:RAD1R-HSA-176264 (Reactome)
RFWD2R-HSA-349444 (Reactome)
RPA complexed to ssDNAArrowR-HSA-176175 (Reactome)
RPA complexed to ssDNAR-HSA-176101 (Reactome)
RPA complexed to ssDNAR-HSA-176250 (Reactome)
RPA heterotrimerR-HSA-176175 (Reactome)
Rad17-RFC complex bound to DNAArrowR-HSA-176101 (Reactome)
Rad17-RFC complex bound to DNAR-HSA-176264 (Reactome)
Rad17-RFC complex bound to DNAmim-catalysisR-HSA-176264 (Reactome)
Rad9-Hus1-Rad1 bound to DNAArrowR-HSA-176264 (Reactome)
TP53 TetramerR-HSA-5633460 (Reactome)
TP53 TetramerR-HSA-5693609 (Reactome)
TP53 TetramerR-HSA-6799332 (Reactome)
Ub-p-S123-CDC25AArrowR-HSA-69598 (Reactome)
Ub-p-S123-CDC25AR-HSA-69600 (Reactome)
UbArrowR-HSA-264458 (Reactome)
UbArrowR-HSA-69600 (Reactome)
UbArrowR-HSA-8852354 (Reactome)
UbR-HSA-264444 (Reactome)
UbR-HSA-6804724 (Reactome)
UbR-HSA-6804879 (Reactome)
UbR-HSA-69598 (Reactome)
Ubiquitin ligasemim-catalysisR-HSA-69598 (Reactome)
WEE1R-HSA-75028 (Reactome)
WEE1mim-catalysisR-HSA-170070 (Reactome)
ZNF385AR-HSA-6803719 (Reactome)
hBUBR1:hBUB3:MAD2*:CDC20 complexArrowR-HSA-141437 (Reactome)
hBUBR1:hBUB3:MAD2*:CDC20 complexR-HSA-141423 (Reactome)
p-5S,T-MDM2ArrowR-HSA-6804955 (Reactome)
p-S,3T-CHEK2ArrowR-HSA-5683792 (Reactome)
p-S,3T-CHEK2mim-catalysisR-HSA-349426 (Reactome)
p-S,3T-CHEK2mim-catalysisR-HSA-69608 (Reactome)
p-S,3T-CHEK2mim-catalysisR-HSA-69685 (Reactome)
p-S,3T-CHEK2mim-catalysisR-HSA-75809 (Reactome)
p-S123-CDC25AArrowR-HSA-69604 (Reactome)
p-S123-CDC25AArrowR-HSA-69608 (Reactome)
p-S123-CDC25AR-HSA-69598 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385A:CDKN1A GeneArrowR-HSA-6803388 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385A:CDKN1A GeneArrowR-HSA-6803801 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385AArrowR-HSA-6803719 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385AR-HSA-6803801 (Reactome)
p-S15,S20-TP53 TetramerArrowR-HSA-6799246 (Reactome)
p-S15,S20-TP53 TetramerArrowR-HSA-69685 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6803719 (Reactome)
p-S15-TP53 TetramerArrowR-HSA-264435 (Reactome)
p-S15-TP53 TetramerArrowR-HSA-5693609 (Reactome)
p-S15-TP53 TetramerArrowR-HSA-6799332 (Reactome)
p-S15-TP53 TetramerR-HSA-6799246 (Reactome)
p-S15-TP53 TetramerR-HSA-69685 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2,MDM4:TP53
ArrowR-HSA-5633460 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2,MDM4:TP53
R-HSA-6804879 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2,MDM4:TP53
mim-catalysisR-HSA-6804879 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2:MDM4
ArrowR-HSA-6804741 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2:MDM4
ArrowR-HSA-6804879 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2:MDM4
R-HSA-5633460 (Reactome)
p-S166,S188-MDM2,MDM4R-HSA-6804741 (Reactome)
p-S166,S188-MDM2:MDM4R-HSA-349455 (Reactome)
p-S166,S188-MDM2:p-S346,S367,S403-MDM4ArrowR-HSA-349426 (Reactome)
p-S166,S188-MDM2:p-S346,S367,S403-MDM4R-HSA-6804724 (Reactome)
p-S166,S188-MDM2:p-S346,S367,S403-MDM4mim-catalysisR-HSA-6804724 (Reactome)
p-S166,S188-MDM2:p-S403-MDM4ArrowR-HSA-349455 (Reactome)
p-S166,S188-MDM2:p-S403-MDM4R-HSA-349426 (Reactome)
p-S166,S188-MDM2R-HSA-6804741 (Reactome)
p-S166,S188-MDM2R-HSA-6804955 (Reactome)
p-S1981,Ac-K3016-ATMTBarR-HSA-6804741 (Reactome)
p-S1981,Ac-K3016-ATMmim-catalysisR-HSA-349444 (Reactome)
p-S1981,Ac-K3016-ATMmim-catalysisR-HSA-349455 (Reactome)
p-S1981,Ac-K3016-ATMmim-catalysisR-HSA-5693609 (Reactome)
p-S1981,Ac-K3016-ATMmim-catalysisR-HSA-6804955 (Reactome)
p-S1981,Ac-K3016-ATMmim-catalysisR-HSA-69889 (Reactome)
p-S216-CDC25C:14-3-3 protein complexArrowR-HSA-75016 (Reactome)
p-S216-CDC25CArrowR-HSA-75010 (Reactome)
p-S216-CDC25CArrowR-HSA-75809 (Reactome)
p-S216-CDC25CR-HSA-75016 (Reactome)
p-S317,S345-CHEK1ArrowR-HSA-176116 (Reactome)
p-S317,S345-CHEK1ArrowR-HSA-69889 (Reactome)
p-S317,S345-CHEK1mim-catalysisR-HSA-6799246 (Reactome)
p-S317,S345-CHEK1mim-catalysisR-HSA-69604 (Reactome)
p-S317,S345-CHEK1mim-catalysisR-HSA-75010 (Reactome)
p-S317,S345-CHEK1mim-catalysisR-HSA-75028 (Reactome)
p-S387-RFWD2:p-S15-TP53R-HSA-264435 (Reactome)
p-S387-RFWD2ArrowR-HSA-264418 (Reactome)
p-S387-RFWD2ArrowR-HSA-264435 (Reactome)
p-S387-RFWD2ArrowR-HSA-349444 (Reactome)
p-S387-RFWD2R-HSA-264418 (Reactome)
p-S387-RFWD2R-HSA-264444 (Reactome)
p-S387-RFWD2mim-catalysisR-HSA-264444 (Reactome)
p-S435-GTSE1:PolyUb-TP53 TetramerArrowR-HSA-8852337 (Reactome)
p-S435-GTSE1:PolyUb-TP53 TetramerArrowR-HSA-8852351 (Reactome)
p-S435-GTSE1:PolyUb-TP53 TetramerR-HSA-8852351 (Reactome)
p-S435-GTSE1:PolyUb-TP53 TetramerR-HSA-8852354 (Reactome)
p-S435-GTSE1ArrowR-HSA-8852354 (Reactome)
p-S435-GTSE1R-HSA-8852337 (Reactome)
p-T68-CHEK2 dimerArrowR-HSA-5683774 (Reactome)
p-T68-CHEK2 dimerR-HSA-5683792 (Reactome)
p-T68-CHEK2 dimermim-catalysisR-HSA-5683792 (Reactome)
p-T68-CHEK2ArrowR-HSA-69891 (Reactome)
p-T68-CHEK2R-HSA-5683774 (Reactome)
p-WEE1ArrowR-HSA-75028 (Reactome)
p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4TBarR-HSA-6804879 (Reactome)
phosphorylated

anaphase promoting

complex (APC/C)
R-HSA-141423 (Reactome)
ubiquitinated phospho-COP1(ser-387)ArrowR-HSA-264444 (Reactome)
ubiquitinated phospho-COP1(ser-387)R-HSA-264458 (Reactome)

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