Cell cycle checkpoints (Homo sapiens)

From WikiPathways

Revision as of 02:47, 14 January 2011 by AlexanderPico (Talk | contribs)
Jump to: navigation, search
4616, 21, 29, 374, 33, 3514, 2452443543224811481025, 27, 455474759, 18, 38, 4215, 20, 31127, 39413, 1923284, 8, 30, 33, 35...40540cytosolReaction using segmented line with waypoints and anchorsnucleoplasmCyclin B:Cdc2 complexADPPhospho-COP1(Ser-387):p53 complexMAD2*CDC20 complexADPCyclin B1:phospho-Cdc2 (Thr 14, Thr 161)ATR-ATRIPChk2phospho-Chk2ubiquitinADPATPADPATP26S proteasomeKinetochore:Mad1:MAD2* ComplexRad17-RFC complexphospho-Cdc25Aphospho-Cdc25C:14-3-3 protein complexAmino AcidChk1Cdc25ChBUBR1phospho-Cdc25ACdc45:CDK:DDK:Mcm10:pre-replicative complexp21ATPphospho-MDM2phosho-COP1(ser-387)Ubiquitinated Phospho-Cdc25AATPphosphorylated anaphase promoting complex (APC/C)14-3-3 proteinsMCC:APC/C complexRad9-Hus1-Rad1 complexADPhBUBR1:hBUB3:MAD2*:CDC20 complexKinetochore Complexphospho-Chk1p53 ser-15 phosphorylatedKinetochore:Mad1:MAD2 ComplexRPA heterotrimerHsMAD2Mad1:kinetochore complexUbiquitin ligasephosph-Cdc25C (Ser 216)phospho-ATM (Ser 1981)Cdc45:CDK:DDK:Mcm10:claspin:pre-replicative complexphospho-Wee1ADPp53 tetramerATPCyclin E:Cdk2 complexesADPATPCdc20ATPATPp53 proteinATPphosph-Cdc25C (Ser 216)Cdc45:CDK:DDK:Mcm10:Activated claspin:pre-replicative complexADPRPA complexed to ssDNARad17-RFC complex bound to DNAATPCyclin B:phospho-Cdc2(Thr 14)HsMad1ATPATPRad9-Hus1-Rad1 bound to DNAphospho-COP1(Ser 387)Cyclin E:Cdk2:p21/p27 complexCOP1ADPADPADPATPCdc25AMAD2*Wee1ADPMdm2p21/p27Persistent single-stranded DNAADPCyclin B1:phospho-Cdc2(Thr 161, Thr 14, Tyr 15)Apoptosis PathwayChk1/Ckk2(Cds1)ATR-ATRIP-RPA-ssDNA signaling complexClaspinMitotic checkpoint protein BUB3ubiquitinated phospho-COP1(ser-387)17, 3416, 26, 373662, 13, 32, 38149ATPWee1Cyclin B1:phospho-Cdc2 (Thr 14, Thr 161)ADPCyclin B1:phospho-Cdc2(Thr 161, Thr 14, Tyr 15)Example of a link to another pathway


Description

No description

Comments

Reactome summation 
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.

Try the New WikiPathways

View approved pathways at the new wikipathways.org.

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Ball HL, Cortez D.; ''ATRIP oligomerization is required for ATR-dependent checkpoint signaling.''; PubMed Europe PMC Scholia
  2. Espinosa JM, Verdun RE, Emerson BM.; ''p53 functions through stress- and promoter-specific recruitment of transcription initiation components before and after DNA damage.''; PubMed Europe PMC Scholia
  3. Namiki Y, Zou L.; ''ATRIP associates with replication protein A-coated ssDNA through multiple interactions.''; PubMed Europe PMC Scholia
  4. Falck J, Mailand N, Syljuåsen RG, Bartek J, Lukas J.; ''The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis.''; PubMed Europe PMC Scholia
  5. Linares LK, Hengstermann A, Ciechanover A, Müller S, Scheffner M.; ''HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53.''; PubMed Europe PMC Scholia
  6. Matsuoka S, Rotman G, Ogawa A, Shiloh Y, Tamai K, Elledge SJ.; ''Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro.''; PubMed Europe PMC Scholia
  7. Sironi L, Mapelli M, Knapp S, De Antoni A, Jeang KT, Musacchio A.; ''Crystal structure of the tetrameric Mad1-Mad2 core complex: implications of a 'safety belt' binding mechanism for the spindle checkpoint.''; PubMed Europe PMC Scholia
  8. Zou L, Liu D, Elledge SJ.; ''Replication protein A-mediated recruitment and activation of Rad17 complexes.''; PubMed Europe PMC Scholia
  9. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ.; ''The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.''; PubMed Europe PMC Scholia
  10. Danielsen JR, Povlsen LK, Villumsen BH, Streicher W, Nilsson J, Wikström M, Bekker-Jensen S, Mailand N.; ''DNA damage-inducible SUMOylation of HERC2 promotes RNF8 binding via a novel SUMO-binding Zinc finger.''; PubMed Europe PMC Scholia
  11. Tibbetts RS, Brumbaugh KM, Williams JM, Sarkaria JN, Cliby WA, Shieh SY, Taya Y, Prives C, Abraham RT.; ''A role for ATR in the DNA damage-induced phosphorylation of p53.''; PubMed Europe PMC Scholia
  12. Bermudez VP, Lindsey-Boltz LA, Cesare AJ, Maniwa Y, Griffith JD, Hurwitz J, Sancar A.; ''Loading of the human 9-1-1 checkpoint complex onto DNA by the checkpoint clamp loader hRad17-replication factor C complex in vitro.''; PubMed Europe PMC Scholia
  13. Ciccia A, Elledge SJ.; ''The DNA damage response: making it safe to play with knives.''; PubMed Europe PMC Scholia
  14. Unsal-Kaçmaz K, Sancar A.; ''Quaternary structure of ATR and effects of ATRIP and replication protein A on its DNA binding and kinase activities.''; PubMed Europe PMC Scholia
  15. Momand J, Zambetti GP, Olson DC, George D, Levine AJ.; ''The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation.''; PubMed Europe PMC Scholia
  16. Chen L, Gilkes DM, Pan Y, Lane WS, Chen J.; ''ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage.''; PubMed Europe PMC Scholia
  17. Cotta-Ramusino C, McDonald ER, Hurov K, Sowa ME, Harper JW, Elledge SJ.; ''A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling.''; PubMed Europe PMC Scholia
  18. Clarke CA, Clarke PR.; ''DNA-dependent phosphorylation of Chk1 and Claspin in a human cell-free system.''; PubMed Europe PMC Scholia
  19. Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, Ziv Y.; ''Enhanced phosphorylation of p53 by ATM in response to DNA damage.''; PubMed Europe PMC Scholia
  20. Monte M, Benetti R, Collavin L, Marchionni L, Del Sal G, Schneider C.; ''hGTSE-1 expression stimulates cytoplasmic localization of p53.''; PubMed Europe PMC Scholia
  21. Foray N, Marot D, Gabriel A, Randrianarison V, Carr AM, Perricaudet M, Ashworth A, Jeggo P.; ''A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein.''; PubMed Europe PMC Scholia
  22. Zhao H, Piwnica-Worms H.; ''ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1.''; PubMed Europe PMC Scholia
  23. Huang L, Yan Z, Liao X, Li Y, Yang J, Wang ZG, Zuo Y, Kawai H, Shadfan M, Ganapathy S, Yuan ZM.; ''The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo.''; PubMed Europe PMC Scholia
  24. Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM.; ''Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53.''; PubMed Europe PMC Scholia
  25. Hang H, Lieberman HB.; ''Physical interactions among human checkpoint control proteins HUS1p, RAD1p, and RAD9p, and implications for the regulation of cell cycle progression.''; PubMed Europe PMC Scholia
  26. Geyer RK, Yu ZK, Maki CG.; ''The MDM2 RING-finger domain is required to promote p53 nuclear export.''; PubMed Europe PMC Scholia
  27. Wang B, Matsuoka S, Ballif BA, Zhang D, Smogorzewska A, Gygi SP, Elledge SJ.; ''Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response.''; PubMed Europe PMC Scholia
  28. Sar F, Lindsey-Boltz LA, Subramanian D, Croteau DL, Hutsell SQ, Griffith JD, Sancar A.; ''Human claspin is a ring-shaped DNA-binding protein with high affinity to branched DNA structures.''; PubMed Europe PMC Scholia
  29. Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, Luo G, Carattini-Rivera S, DeMayo F, Bradley A, Donehower LA, Elledge SJ.; ''Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint.''; PubMed Europe PMC Scholia
  30. Li J, Stern DF.; ''DNA damage regulates Chk2 association with chromatin.''; PubMed Europe PMC Scholia
  31. Campbell MS, Chan GK, Yen TJ.; ''Mitotic checkpoint proteins HsMAD1 and HsMAD2 are associated with nuclear pore complexes in interphase.''; PubMed Europe PMC Scholia
  32. Chehab NH, Malikzay A, Appel M, Halazonetis TD.; ''Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53.''; PubMed Europe PMC Scholia
  33. Plafker SM, Plafker KS, Weissman AM, Macara IG.; ''Ubiquitin charging of human class III ubiquitin-conjugating enzymes triggers their nuclear import.''; PubMed Europe PMC Scholia
  34. Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB, Siliciano JD.; ''Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.''; PubMed Europe PMC Scholia
  35. Bulavin DV, Higashimoto Y, Demidenko ZN, Meek S, Graves P, Phillips C, Zhao H, Moody SA, Appella E, Piwnica-Worms H, Fornace AJ.; ''Dual phosphorylation controls Cdc25 phosphatases and mitotic entry.''; PubMed Europe PMC Scholia
  36. Peng CY, Graves PR, Thoma RS, Wu Z, Shaw AS, Piwnica-Worms H.; ''Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216.''; PubMed Europe PMC Scholia
  37. Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B.; ''Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53.''; PubMed Europe PMC Scholia
  38. Pant V, Xiong S, Iwakuma T, Quintás-Cardama A, Lozano G.; ''Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability.''; PubMed Europe PMC Scholia
  39. Graves PR, Lovly CM, Uy GL, Piwnica-Worms H.; ''Localization of human Cdc25C is regulated both by nuclear export and 14-3-3 protein binding.''; PubMed Europe PMC Scholia
  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 proteins REACT_2548 (Reactome)
26S proteasome ComplexREACT_2353 (Reactome)
ADP Metabolite16761 (ChEBI)
ATP Metabolite15422 (ChEBI)
ATR-ATRIP ComplexREACT_7002 (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.
ATR-ATRIP-RPA-

ssDNA signaling complex

ComplexREACT_7037 (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.
Amino Acid REACT_2474 (Reactome)
Apoptosis PathwayPathwayWP254 (WikiPathways)
COP1 ProteinQ8NHY2 (UniProt)
Cdc20 ProteinQ12834 (UniProt)
Cdc25A ProteinP30304 (UniProt)
Cdc25C ProteinP30307 (UniProt)
Cdc45:CDK:DDK:

Mcm10:Activated claspin:pre-replicative complex

ComplexREACT_7262 (Reactome)
Cdc45:CDK:DDK:

Mcm10:claspin:pre- replicative complex

ComplexREACT_7273 (Reactome)
Cdc45:CDK:DDK:

Mcm10:pre-replicative complex

ComplexREACT_4546 (Reactome)
Chk1 ProteinO14757 (UniProt)
Chk1/Ckk2(Cds1) REACT_5826 (Reactome)
Chk2 ProteinO96017-12 (UniProt)
Claspin ProteinQ9HAW4 (UniProt)
Cyclin B1:phospho-Cdc2

(Thr 161, Thr 14, Tyr 15)

ComplexREACT_6704 (Reactome)
Cyclin B1:phospho-Cdc2

(Thr 14, Thr 161)

ComplexREACT_6474 (Reactome)
Cyclin B:Cdc2

complex

ComplexREACT_6447 (Reactome)
Cyclin B:phospho-

Cdc2(Thr 14)

ComplexREACT_6524 (Reactome)
Cyclin E:Cdk2

complexes

ComplexREACT_5247 (Reactome)
Cyclin E:Cdk2:p21/p27

complex

ComplexREACT_3804 (Reactome)
HsMAD2 ProteinQ13257 (UniProt)
HsMad1 ProteinQ9Y6D9 (UniProt)
Kinetochore

Complex

REACT_5901 (Reactome)
Kinetochore:Mad1:

MAD2 Complex

ComplexREACT_4828 (Reactome) Mad2 binds to the Mad1:Kinetochore and undergoes a major conformational change within the complex to assume the form Mad2*.
Kinetochore:Mad1:

MAD2* Complex

ComplexREACT_5238 (Reactome)
MAD2* ProteinQ13257 (UniProt)
MAD2*CDC20

complex

ComplexREACT_2295 (Reactome) Activated Mad2 upon release from kinetochores binds and sequesters Cdc20 from activating the APC.
MCC:APC/C complex ComplexREACT_3955 (Reactome)
Mad1:kinetochore

complex

ComplexREACT_5632 (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.
Mdm2 ProteinQ00987 (UniProt)
Mitotic checkpoint

protein BUB3

ProteinO43684 (UniProt)
Persistent single-

stranded DNA

REACT_7801 (Reactome)
Phospho-COP1(Ser-387):

p53 complex

ComplexREACT_21189 (Reactome)
RPA complexed to

ssDNA

ComplexREACT_7172 (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 heterotrimer ComplexREACT_3427 (Reactome)
Rad17-RFC complex ComplexREACT_7804 (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.

Rad17-RFC complex

bound to DNA

ComplexREACT_7502 (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

complex

ComplexREACT_7593 (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.
Rad9-Hus1-Rad1 bound

to DNA

ComplexREACT_7267 (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.
Ubiquitin ligase REACT_4282 (Reactome)
Ubiquitinated

Phospho-Cdc25A

ComplexREACT_4164 (Reactome) A number of ubiquitin moeities are covalently added to the Cdc25A, which marks it for proteolytic degradation.
Wee1 ProteinP30291 (UniProt)
hBUBR1 ProteinO60566 (UniProt)
hBUBR1:hBUB3:

MAD2*:CDC20 complex

ComplexREACT_5836 (Reactome)
p21 ProteinP38936 (UniProt)
p21/p27 ProteinREACT_8306 (Reactome)
p53 protein ProteinP04637 (UniProt)
p53 ser-15

phosphorylated

ProteinP04637 (UniProt)
p53 tetramer ComplexREACT_20792 (Reactome)
phosho-COP1(ser-387) ProteinQ8NHY2 (UniProt)
phosph-Cdc25C (Ser 216) ProteinP30307 (UniProt)
phospho-ATM (Ser

1981)

ProteinQ13315 (UniProt)
phospho-COP1(Ser 387) ProteinQ8NHY2 (UniProt)
phospho-Cdc25A ProteinP30304 (UniProt)
phospho-Cdc25C:14-3-

3 protein complex

ComplexREACT_4474 (Reactome)
phospho-Chk1 ProteinO14757 (UniProt)
phospho-Chk2 ProteinO96017-12 (UniProt)
phospho-MDM2 ProteinQ00987 (UniProt)
phospho-Wee1 ProteinP30291 (UniProt)
phosphorylated anaphase

promoting complex (APC/C)

ComplexREACT_7058 (Reactome)
ubiquitin ProteinREACT_3316 (Reactome)
ubiquitinated phospho-

COP1(ser-387)

ComplexREACT_21146 (Reactome)

Annotated Interactions

No annotated interactions

Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP1775"
Personal tools