HDR through Homologous Recombination or Single Strand Annealing (Homo sapiens)
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For both HRR and SSA to occur, the ends of the DNA DSB must be processed (resected) to generate lengthy 3' ssDNA tails, and the resulting ssDNA coated with RPA complexes, triggering ATR activation and signaling.<p>After the resection step, BRCA2 and RAD51 trigger HRR, a very accurate process in which the 3'-ssDNA overhang invades a sister chromatid, base pairs with the complementary strand of the sister chromatid DNA duplex, creating a D-loop, and uses the complementary sister chromatid strand as a template for DNA repair synthesis that bridges the DSB.<p>The SSA is triggered when 3'-ssDNA overhangs created in the resection step contain highly homologous direct repeats. In a process involving RAD52, the direct repeats in each 3'-ssDNA overhang become annealed, the unannealed 3'-flaps excised, and structures then processed by DNA repair synthesis. SSA results in the loss of one of the annealed repeats and the DNA sequence between the two repeats. Therefore, SSA is error-prone and is probably used as a backup for HRR, with RAD52 loss-of-function mutations being synthetically lethal with mutations in HRR genes, such as BRCA2 (reviewed by Ciccia and Elledge 2010). View original pathway at:Reactome.</div>
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- Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, Grossman S, Wahrer DC, Sgroi DC, Lane WS, Haber DA, Livingston DM.; ''BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function.''; PubMed Europe PMC Scholia
- Yin Y, Seifert A, Chua JS, Maure JF, Golebiowski F, Hay RT.; ''SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damage.''; PubMed Europe PMC Scholia
- Chun J, Buechelmaier ES, Powell SN.; ''Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway.''; PubMed Europe PMC Scholia
- Liu S, Opiyo SO, Manthey K, Glanzer JG, Ashley AK, Amerin C, Troksa K, Shrivastav M, Nickoloff JA, Oakley GG.; ''Distinct roles for DNA-PK, ATM and ATR in RPA phosphorylation and checkpoint activation in response to replication stress.''; PubMed Europe PMC Scholia
- Jensen RB, Carreira A, Kowalczykowski SC.; ''Purified human BRCA2 stimulates RAD51-mediated recombination.''; PubMed Europe PMC Scholia
- Mallette FA, Mattiroli F, Cui G, Young LC, Hendzel MJ, Mer G, Sixma TK, Richard S.; ''RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites.''; PubMed Europe PMC Scholia
- McIlwraith MJ, Van Dyck E, Masson JY, Stasiak AZ, Stasiak A, West SC.; ''Reconstitution of the strand invasion step of double-strand break repair using human Rad51 Rad52 and RPA proteins.''; PubMed Europe PMC Scholia
- Lee J, Gold DA, Shevchenko A, Shevchenko A, Dunphy WG.; ''Roles of replication fork-interacting and Chk1-activating domains from Claspin in a DNA replication checkpoint response.''; PubMed Europe PMC Scholia
- Kolpashchikov DM, Khodyreva SN, Khlimankov DY, Wold MS, Favre A, Lavrik OI.; ''Polarity of human replication protein A binding to DNA.''; PubMed Europe PMC Scholia
- Wang H, Shi LZ, Wong CC, Han X, Hwang PY, Truong LN, Zhu Q, Shao Z, Chen DJ, Berns MW, Yates JR, Chen L, Wu X.; ''The interaction of CtIP and Nbs1 connects CDK and ATM to regulate HR-mediated double-strand break repair.''; PubMed Europe PMC Scholia
- Wilson KA, Stern DF.; ''NFBD1/MDC1, 53BP1 and BRCA1 have both redundant and unique roles in the ATM pathway.''; PubMed Europe PMC Scholia
- Murphy AK, Fitzgerald M, Ro T, Kim JH, Rabinowitsch AI, Chowdhury D, Schildkraut CL, Borowiec JA.; ''Phosphorylated RPA recruits PALB2 to stalled DNA replication forks to facilitate fork recovery.''; PubMed Europe PMC Scholia
- Friedberg EC, Lehmann AR, Fuchs RP.; ''Trading places: how do DNA polymerases switch during translesion DNA synthesis?''; PubMed Europe PMC Scholia
- McIlwraith MJ, Vaisman A, Liu Y, Fanning E, Woodgate R, West SC.; ''Human DNA polymerase eta promotes DNA synthesis from strand invasion intermediates of homologous recombination.''; PubMed Europe PMC Scholia
- Gatei M, Young D, Cerosaletti KM, Desai-Mehta A, Spring K, Kozlov S, Lavin MF, Gatti RA, Concannon P, Khanna K.; ''ATM-dependent phosphorylation of nibrin in response to radiation exposure.''; PubMed Europe PMC Scholia
- 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
- Matsuda T, Bebenek K, Masutani C, Hanaoka F, Kunkel TA.; ''Low fidelity DNA synthesis by human DNA polymerase-eta.''; PubMed Europe PMC Scholia
- Davies OR, Forment JV, Sun M, Belotserkovskaya R, Coates J, Galanty Y, Demir M, Morton CR, Rzechorzek NJ, Jackson SP, Pellegrini L.; ''CtIP tetramer assembly is required for DNA-end resection and repair.''; PubMed Europe PMC Scholia
- Bocquet N, Bizard AH, Abdulrahman W, Larsen NB, Faty M, Cavadini S, Bunker RD, Kowalczykowski SC, Cejka P, Hickson ID, Thomä NH.; ''Structural and mechanistic insight into Holliday-junction dissolution by topoisomerase IIIα and RMI1.''; PubMed Europe PMC Scholia
- Stasiak AZ, Larquet E, Stasiak A, Müller S, Engel A, Van Dyck E, West SC, Egelman EH.; ''The human Rad52 protein exists as a heptameric ring.''; PubMed Europe PMC Scholia
- Jackson MD, Denu JM.; ''Structural identification of 2'- and 3'-O-acetyl-ADP-ribose as novel metabolites derived from the Sir2 family of beta -NAD+-dependent histone/protein deacetylases.''; PubMed Europe PMC Scholia
- Ahnesorg P, Smith P, Jackson SP.; ''XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining.''; PubMed Europe PMC Scholia
- Li X, Heyer WD.; ''RAD54 controls access to the invading 3'-OH end after RAD51-mediated DNA strand invasion in homologous recombination in Saccharomyces cerevisiae.''; PubMed Europe PMC Scholia
- Wang J, Aroumougame A, Lobrich M, Li Y, Chen D, Chen J, Gong Z.; ''PTIP associates with Artemis to dictate DNA repair pathway choice.''; PubMed Europe PMC Scholia
- Ohashi E, Bebenek K, Matsuda T, Feaver WJ, Gerlach VL, Friedberg EC, Ohmori H, Kunkel TA.; ''Fidelity and processivity of DNA synthesis by DNA polymerase kappa, the product of the human DINB1 gene.''; PubMed Europe PMC Scholia
- Wang B, Matsuoka S, Carpenter PB, Elledge SJ.; ''53BP1, a mediator of the DNA damage checkpoint.''; PubMed Europe PMC Scholia
- Mortusewicz O, Leonhardt H.; ''XRCC1 and PCNA are loading platforms with distinct kinetic properties and different capacities to respond to multiple DNA lesions.''; PubMed Europe PMC Scholia
- Stucki M, Clapperton JA, Mohammad D, Yaffe MB, Smerdon SJ, Jackson SP.; ''MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks.''; PubMed Europe PMC Scholia
- Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ.; ''MDC1 is a mediator of the mammalian DNA damage checkpoint.''; PubMed Europe PMC Scholia
- Liu Y, Masson JY, Shah R, O'Regan P, West SC.; ''RAD51C is required for Holliday junction processing in mammalian cells.''; PubMed Europe PMC Scholia
- Su HL, Li SS.; ''Molecular features of human ubiquitin-like SUMO genes and their encoded proteins.''; PubMed Europe PMC Scholia
- 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
- Wang X, Zou L, Lu T, Bao S, Hurov KE, Hittelman WN, Elledge SJ, Li L.; ''Rad17 phosphorylation is required for claspin recruitment and Chk1 activation in response to replication stress.''; PubMed Europe PMC Scholia
- Chen L, Nievera CJ, Lee AY, Wu X.; ''Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair.''; PubMed Europe PMC Scholia
History
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External references
DataNodes
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Name | Type | Database reference | Comment |
---|---|---|---|
(SLX1A:SLX4:MUS81:EME1,EME2),GEN1 | Complex | R-HSA-5686489 (Reactome) | |
2'-O-acetyl-ADP-ribose | Metabolite | CHEBI:76279 (ChEBI) | |
3'
overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-T309-RAD51:p-T3387-BRCA2:BCDX2 complex | Complex | R-HSA-5685343 (Reactome) | |
3'
overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-T309-RAD51:p-T3387-BRCA2 | Complex | R-HSA-5685317 (Reactome) | |
3'
overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1 | Complex | R-HSA-5684128 (Reactome) | |
3'
short overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1 | Complex | R-HSA-5685989 (Reactome) | |
3'
short overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex | Complex | R-HSA-5685983 (Reactome) | |
3' overhanging DNA at resected DSB ends | R-NUL-75156 (Reactome) | ||
3' short overhanging ssDNA-DSBs | R-NUL-5685984 (Reactome) | ||
ADP | Metabolite | CHEBI:16761 (ChEBI) | |
ATP | Metabolite | CHEBI:15422 (ChEBI) | |
ATR | Protein | Q13535 (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 | Complex | R-HSA-5685039 (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 | Complex | R-HSA-5684874 (Reactome) | |
ATR:ATRIP:p-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:TIMELESS:TIPIN:p-T916,S945-CLSPN:CHEK1 | Complex | R-HSA-5684883 (Reactome) | |
ATR:ATRIP:p-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 | Complex | R-HSA-5685162 (Reactome) | |
ATR:ATRIP | Complex | R-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 | Protein | Q8WXE1 (Uniprot-TrEMBL) | |
Ac-K432,K526,K604-RBBP8 | Protein | Q99708 (Uniprot-TrEMBL) | |
Ac-K432,K526,K604-RBBP8 homotetramer | Complex | R-HSA-5685960 (Reactome) | |
BABAM1 | Protein | Q9NWV8 (Uniprot-TrEMBL) | |
BABAM1 | Protein | Q9NWV8 (Uniprot-TrEMBL) | |
BCDX2 complex | Complex | R-HSA-5685316 (Reactome) | |
BLM | Protein | P54132 (Uniprot-TrEMBL) | |
BLM:TOP3A:RMI1:RMI2:SPIDR | Complex | R-HSA-5686409 (Reactome) | |
BLM:TOP3A:RMI1:RMI2 | Complex | R-HSA-5685972 (Reactome) | |
BRCA2 | Protein | P51587 (Uniprot-TrEMBL) | |
BRCC3 | Protein | P46736 (Uniprot-TrEMBL) | |
BRCC3 | Protein | P46736 (Uniprot-TrEMBL) | |
BRE | Protein | Q9NXR7 (Uniprot-TrEMBL) | |
BRE | Protein | Q9NXR7 (Uniprot-TrEMBL) | |
CCNA1 | Protein | P78396 (Uniprot-TrEMBL) | |
CCNA2 | Protein | P20248 (Uniprot-TrEMBL) | |
CCNA:p-T160-CDK2 | Complex | R-HSA-187952 (Reactome) | |
CHEK1 | Protein | O14757 (Uniprot-TrEMBL) | |
CHEK1 | Protein | O14757 (Uniprot-TrEMBL) | |
CX3 complex | Complex | R-HSA-5685311 (Reactome) | |
Cleaved D-Loop:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | Complex | R-HSA-5686432 (Reactome) | |
Cleaved
Holliday Junction:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | Complex | R-HSA-5686493 (Reactome) | |
Cleaved D-loop | R-NUL-5686442 (Reactome) | ||
D-Loop:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | Complex | R-HSA-5685826 (Reactome) | |
D-Loop:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1 | Complex | R-HSA-5685658 (Reactome) | |
DNA
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:SUMO2:K1840,p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-5S,2T-BRCA1-A complex | Complex | R-HSA-5684053 (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-5S,2T-BRCA1-A complex | Complex | R-HSA-5683808 (Reactome) | |
DNA DSB:p-MRN:p-S1981,Ac-K3016-ATM:KAT5 | Complex | R-HSA-5682162 (Reactome) | |
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:CCNA:p-T160-CDK2:RBBP8 | Complex | R-HSA-5684094 (Reactome) | |
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-BRCA1-C complex | Complex | R-HSA-5684107 (Reactome) | |
DNA DSBs:p-MRN:p-S327,T847,T859-RBBP8:p-S1981,Ac-K3016-ATM:KAT5 | Complex | R-HSA-5684135 (Reactome) | |
DNA DSBs:p-MRN:p-S327,T847-RBBP8:p-S1981,Ac-K3016-ATM:KAT5 | Complex | R-HSA-5684095 (Reactome) | |
DNA DSB with annealed 3' overhanging ssDNA and flaps | R-NUL-5686618 (Reactome) | ||
DNA Double Strand Break Response | Pathway | R-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 | Protein | P51530 (Uniprot-TrEMBL) | |
EME1 | Protein | Q96AY2 (Uniprot-TrEMBL) | |
EME1,EME2 | Complex | R-HSA-5686454 (Reactome) | |
EME2 | Protein | A4GXA9 (Uniprot-TrEMBL) | |
ERCC1 | Protein | P07992 (Uniprot-TrEMBL) | |
ERCC1:ERCC4 | Complex | R-HSA-109943 (Reactome) | |
ERCC4 | Protein | Q92889 (Uniprot-TrEMBL) | |
EXO1 | Protein | Q9UQ84 (Uniprot-TrEMBL) | |
EXO1,DNA2:BLM,WRN | Complex | R-HSA-5685980 (Reactome) | |
Extended D-Loop:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | Complex | R-HSA-5686104 (Reactome) | |
Extended D-loop | R-NUL-5686092 (Reactome) | ||
Flap | R-NUL-68454 (Reactome) | ||
GEN1 | Protein | Q17RS7 (Uniprot-TrEMBL) | |
H2BFS | Protein | P57053 (Uniprot-TrEMBL) | |
H2O | Metabolite | CHEBI:15377 (ChEBI) | |
HERC2-SUMO1 | Protein | P63165 (Uniprot-TrEMBL) | |
HIST1H2BA | Protein | Q96A08 (Uniprot-TrEMBL) | |
HIST1H2BB | Protein | P33778 (Uniprot-TrEMBL) | |
HIST1H2BC | Protein | P62807 (Uniprot-TrEMBL) | |
HIST1H2BD | Protein | P58876 (Uniprot-TrEMBL) | |
HIST1H2BH | Protein | Q93079 (Uniprot-TrEMBL) | |
HIST1H2BJ | Protein | P06899 (Uniprot-TrEMBL) | |
HIST1H2BK | Protein | O60814 (Uniprot-TrEMBL) | |
HIST1H2BL | Protein | Q99880 (Uniprot-TrEMBL) | |
HIST1H2BM | Protein | Q99879 (Uniprot-TrEMBL) | |
HIST1H2BN | Protein | Q99877 (Uniprot-TrEMBL) | |
HIST1H2BO | Protein | P23527 (Uniprot-TrEMBL) | |
HIST2H2BE | Protein | Q16778 (Uniprot-TrEMBL) | |
HIST3H2BB | Protein | Q8N257 (Uniprot-TrEMBL) | |
HIST3H3 | Protein | Q16695 (Uniprot-TrEMBL) | |
HUS1 | Protein | O60921 (Uniprot-TrEMBL) | |
Heteroduplex DNA with D-loop structure with extended pairing between invading strand and complementary heteroduplex strand | R-NUL-83893 (Reactome) | ||
Holliday Junction:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | Complex | R-HSA-5686228 (Reactome) | |
Holliday structure | R-NUL-75220 (Reactome) | ||
K48PolyUb,SUMO2-K1840,p-5T-MDC1 | Protein | Q14676 (Uniprot-TrEMBL) | |
K48PolyUb:SUMO2:K1840,p-5T-MDC1 dimer | Complex | R-HSA-5684077 (Reactome) | |
K63PolyUb-K14,K16,p-S139-H2AFX | Protein | P16104 (Uniprot-TrEMBL) | |
K63PolyUb:K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome | Complex | R-HSA-5682998 (Reactome) | |
KAT5 | Protein | Q92993 (Uniprot-TrEMBL) | |
KAT5 | Protein | Q92993 (Uniprot-TrEMBL) | |
MDC1-SUMO2 | Protein | P61956 (Uniprot-TrEMBL) | |
MRE11A | Protein | P49959 (Uniprot-TrEMBL) | |
MUS81 | Protein | Q96NY9 (Uniprot-TrEMBL) | |
MUS81:EME1,EME2 | Complex | R-HSA-5686435 (Reactome) | |
MUS81 | Protein | Q96NY9 (Uniprot-TrEMBL) | |
Me2K21-HIST1H4 | Protein | P62805 (Uniprot-TrEMBL) | |
MonoUb-K164-PCNA | Protein | P12004 (Uniprot-TrEMBL) | |
NAD+ | Metabolite | CHEBI:15846 (ChEBI) | |
NAM | Metabolite | CHEBI:17154 (ChEBI) | |
Nonhomologous End-Joining (NHEJ) | Pathway | R-HSA-5693571 (Reactome) | The nonhomologous end joining (NHEJ) pathway is initiated in response to the formation of DNA double-strand breaks (DSBs) induced by DNA-damaging agents, such as ionizing radiation. DNA DSBs are recognized by the MRN complex (MRE11A:RAD50:NBN), leading to ATM activation and ATM-dependent recruitment of a number of DNA damage checkpoint and repair proteins to DNA DSB sites (Lee and Paull 2005). The ATM phosphorylated MRN complex, MDC1 and H2AFX-containing nucleosomes (gamma-H2AX) serve as scaffolds for the formation of nuclear foci known as ionizing radiation induced foci (IRIF) (Gatei et al. 2000, Paull et al. 2000, Stewart et al. 2003, Stucki et al. 2005). Ultimately, both BRCA1:BARD1 heterodimers and TP53BP1 (53BP1) are recruited to IRIF (Wang et al. 2007, Pei et al. 2011, Mallette et al. 2012), which is necessary for ATM-mediated CHEK2 activation (Wang et al. 2002, Wilson et al. 2008). In G1 cells, TP53BP1 promotes NHEJ by recruiting RIF1 and PAX1IP, which displaces BRCA1:BARD1 and associated proteins from the DNA DSB site and prevents resection of DNA DSBs needed for homologous recombination repair (HRR) (Escribano-Diaz et al. 2013, Zimmermann et al. 2013, Callen et al. 2013). TP53BP1 also plays an important role in ATM-mediated phosphorylation of DCLRE1C (ARTEMIS) (Riballo et al. 2004, Wang et al. 2014). Ku70:Ku80 heterodimer (also known as the Ku complex or XRCC5:XRCC6) binds DNA DSB ends, competing away the MRN complex and preventing MRN-mediated resection of DNA DSB ends (Walker et al. 2001, Sun et al. 2012). The catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs, PRKDC) is then recruited to DNA-bound Ku to form the DNA-PK holoenzyme. Two DNA-PK complexes, one at each side of the break, bring DNA DSB ends together, joining them in a synaptic complex (Gottlieb 1993, Yoo and Dynan 2000). DNA-PK complex recruits DCLRE1C (ARTEMIS) to DNA DSB ends (Ma et al. 2002). PRKDC-mediated phosphorylation of DCLRE1C, as well as PRKDC autophosphorylation, enables DCLRE1C to trim 3'- and 5'-overhangs at DNA DSBs, preparing them for ligation (Ma et al. 2002, Ma et al. 2005, Niewolik et al. 2006). The binding of inositol phosphate may additionally stimulate the catalytic activity of PRKDC (Hanakahi et al. 2000). Other factors, such as polynucleotide kinase (PNK), TDP1 or TDP2 may remove unligatable damaged nucleotides from 5'- and 3'-ends of the DSB, converting them to ligatable substrates (Inamdar et al. 2002, Gomez-Herreros et al. 2013). DNA ligase 4 (LIG4) in complex with XRCC4 (XRCC4:LIG4) is recruited to ligatable DNA DSB ends together with the XLF (NHEJ1) homodimer and DNA polymerases mu (POLM) and/or lambda (POLL) (McElhinny et al. 2000, Hsu et al. 2002, Malu et al. 2002, Ahnesorg et al. 2006, Mahajan et al. 2002, Lee et al. 2004, Fan and Wu 2004). After POLL and/or POLM fill 1- or 2-nucleotide long single strand gaps at aligned DNA DSB ends, XRCC4:LIG4 performs the ligation of broken DNA strands, thus completing NHEJ. The presence of NHEJ1 homodimer facilitates the ligation step, especially at mismatched DSB ends (Tsai et al. 2007). Depending on other types of DNA damage present at DNA DSBs, NHEJ can result in error-free products, produce dsDNA with microdeletions and/or mismatched bases, or result in translocations (reviewed by Povrik et al. 2012). |
PALB2 | Protein | Q86YC2 (Uniprot-TrEMBL) | |
PALB2 | Protein | Q86YC2 (Uniprot-TrEMBL) | |
PCNA | Protein | P12004 (Uniprot-TrEMBL) | |
PCNA:POLD,POLE,POLH,POLK:RPA:RFC | Complex | R-HSA-5686084 (Reactome) | |
PIAS4 | Protein | Q8N2W9 (Uniprot-TrEMBL) | |
PIAS4 | Protein | Q8N2W9 (Uniprot-TrEMBL) | |
POLD1 | Protein | P28340 (Uniprot-TrEMBL) | |
POLD2 | Protein | P49005 (Uniprot-TrEMBL) | |
POLD3 | Protein | Q15054 (Uniprot-TrEMBL) | |
POLD4 | Protein | Q9HCU8 (Uniprot-TrEMBL) | |
POLE | Protein | Q07864 (Uniprot-TrEMBL) | |
POLE2 | Protein | P56282 (Uniprot-TrEMBL) | |
POLH | Protein | Q9Y253 (Uniprot-TrEMBL) | |
POLK | Protein | Q9UBT6 (Uniprot-TrEMBL) | |
PPP4C | Protein | P60510 (Uniprot-TrEMBL) | |
PPP4C:PPP4R2 | Complex | R-HSA-5687751 (Reactome) | |
PPP4R2 | Protein | Q9NY27 (Uniprot-TrEMBL) | |
PPi | Metabolite | CHEBI:29888 (ChEBI) | |
Pi | Metabolite | CHEBI:18367 (ChEBI) | |
RAD1 | Protein | O60671 (Uniprot-TrEMBL) | |
RAD17 | Protein | O75943 (Uniprot-TrEMBL) | |
RAD17:RFC | Complex | R-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 | Protein | Q92878 (Uniprot-TrEMBL) | |
RAD51 | Protein | Q06609 (Uniprot-TrEMBL) | |
RAD51:p-Y104-RAD52:p-RPA:ATR:ATRIP: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 | Complex | R-HSA-5693590 (Reactome) | |
RAD51:p-Y104-RAD52:p-RPA:ATR:ATRIP:DNA DSBs with annealed 3' ssDNA overhangs and displaced flaps: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 | Complex | R-HSA-5686613 (Reactome) | |
RAD51AP1 | Protein | Q96B01 (Uniprot-TrEMBL) | |
RAD51AP1 | Protein | Q96B01 (Uniprot-TrEMBL) | |
RAD51B | Protein | O15315 (Uniprot-TrEMBL) | |
RAD51B | Protein | O15315 (Uniprot-TrEMBL) | |
RAD51C | Protein | O43502 (Uniprot-TrEMBL) | |
RAD51C | Protein | O43502 (Uniprot-TrEMBL) | |
RAD51D | Protein | O75771 (Uniprot-TrEMBL) | |
RAD51D | Protein | O75771 (Uniprot-TrEMBL) | |
RAD51 | Protein | Q06609 (Uniprot-TrEMBL) | |
RAD52 | Protein | P43351 (Uniprot-TrEMBL) | |
RAD52 heptamer | Complex | R-HSA-83899 (Reactome) | |
RAD52 | Protein | P43351 (Uniprot-TrEMBL) | |
RAD9:HUS1:RAD1 | Complex | R-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 | Protein | Q99638 (Uniprot-TrEMBL) | |
RAD9B | Protein | Q6WBX8 (Uniprot-TrEMBL) | |
RBBP8 | Protein | Q99708 (Uniprot-TrEMBL) | |
RBBP8 homotetramer | Complex | R-HSA-5684097 (Reactome) | |
RFC1 | Protein | P35251 (Uniprot-TrEMBL) | |
RFC2 | Protein | P35250 (Uniprot-TrEMBL) | |
RFC3 | Protein | P40938 (Uniprot-TrEMBL) | |
RFC4 | Protein | P35249 (Uniprot-TrEMBL) | |
RFC5 | Protein | P40937 (Uniprot-TrEMBL) | |
RHNO1 | Protein | Q9BSD3 (Uniprot-TrEMBL) | |
RHNO1 | Protein | Q9BSD3 (Uniprot-TrEMBL) | |
RMI1 | Protein | Q9H9A7 (Uniprot-TrEMBL) | |
RMI2 | Protein | Q96E14 (Uniprot-TrEMBL) | |
RNF168 | Protein | Q8IYW5 (Uniprot-TrEMBL) | |
RNF168 | Protein | Q8IYW5 (Uniprot-TrEMBL) | |
RNF4 | Protein | P78317 (Uniprot-TrEMBL) | |
RNF4 homodimer | Complex | R-HSA-5684073 (Reactome) | |
RNF8 | Protein | O76064 (Uniprot-TrEMBL) | |
RNF8:Zn2+ | Complex | R-HSA-5682540 (Reactome) | |
RPA heterotrimer | Complex | R-HSA-68462 (Reactome) | |
RPA1 | Protein | P27694 (Uniprot-TrEMBL) | |
RPA2 | Protein | P15927 (Uniprot-TrEMBL) | |
RPA3 | Protein | P35244 (Uniprot-TrEMBL) | |
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 | Complex | R-HSA-5693552 (Reactome) | |
RPS27A(1-76) | Protein | P62979 (Uniprot-TrEMBL) | |
RTEL1 | Protein | Q9NZ71 (Uniprot-TrEMBL) | |
SIRT6 | Protein | Q8N6T7 (Uniprot-TrEMBL) | |
SLX1A | Protein | Q9BQ83 (Uniprot-TrEMBL) | |
SLX1A:SLX4:MUS81:EME1,EME2 | Complex | R-HSA-5686474 (Reactome) | |
SLX1A:SLX4 | Complex | R-HSA-5686480 (Reactome) | |
SLX4 | Protein | Q8IY92 (Uniprot-TrEMBL) | |
SPIDR | Protein | Q14159 (Uniprot-TrEMBL) | |
SPIDR | Protein | Q14159 (Uniprot-TrEMBL) | |
SSB-dsDNA with inter-SSA deletion | R-NUL-5686662 (Reactome) | ||
SUMO1:p-T4827-HERC2 | Complex | R-HSA-5682612 (Reactome) | |
SUMO2-C93-UBE2I | Protein | P63279 (Uniprot-TrEMBL) | |
SUMO2-K1840,p-5T-MDC1 | Protein | Q14676 (Uniprot-TrEMBL) | |
SUMO2:UBE2I | Complex | R-HSA-2993778 (Reactome) | |
Sister Chromatid Arm with Crossover | R-NUL-5686464 (Reactome) | ||
Sister Chromosomal Arm | R-NUL-1638790 (Reactome) | ||
TIMELESS | Protein | Q9UNS1 (Uniprot-TrEMBL) | |
TIMELESS:TIPIN | Complex | R-HSA-5684985 (Reactome) | |
TIPIN | Protein | Q9BVW5 (Uniprot-TrEMBL) | |
TOP3A | Protein | Q13472 (Uniprot-TrEMBL) | |
TOPBP1 | Protein | Q92547 (Uniprot-TrEMBL) | |
TOPBP1 | Protein | Q92547 (Uniprot-TrEMBL) | |
UBA52(1-76) | Protein | P62987 (Uniprot-TrEMBL) | |
UBB(1-76) | Protein | P0CG47 (Uniprot-TrEMBL) | |
UBB(153-228) | Protein | P0CG47 (Uniprot-TrEMBL) | |
UBB(77-152) | Protein | P0CG47 (Uniprot-TrEMBL) | |
UBC(1-76) | Protein | P0CG48 (Uniprot-TrEMBL) | |
UBC(153-228) | Protein | P0CG48 (Uniprot-TrEMBL) | |
UBC(229-304) | Protein | P0CG48 (Uniprot-TrEMBL) | |
UBC(305-380) | Protein | P0CG48 (Uniprot-TrEMBL) | |
UBC(381-456) | Protein | P0CG48 (Uniprot-TrEMBL) | |
UBC(457-532) | Protein | P0CG48 (Uniprot-TrEMBL) | |
UBC(533-608) | Protein | P0CG48 (Uniprot-TrEMBL) | |
UBC(609-684) | Protein | P0CG48 (Uniprot-TrEMBL) | |
UBC(77-152) | Protein | P0CG48 (Uniprot-TrEMBL) | |
UBE2I-G93-SUMO2 | Protein | P61956 (Uniprot-TrEMBL) | |
UBE2I | Protein | P63279 (Uniprot-TrEMBL) | |
UBE2N | Protein | P61088 (Uniprot-TrEMBL) | |
UBE2N:UBE2V2 | Complex | R-HSA-5682542 (Reactome) | |
UBE2V2 | Protein | Q15819 (Uniprot-TrEMBL) | |
UIMC1 | Protein | Q96RL1 (Uniprot-TrEMBL) | |
UIMC1 | Protein | Q96RL1 (Uniprot-TrEMBL) | |
WHSC1 | Protein | O96028 (Uniprot-TrEMBL) | |
WRN | Protein | Q14191 (Uniprot-TrEMBL) | |
XRCC2 | Protein | O43543 (Uniprot-TrEMBL) | |
XRCC2 | Protein | O43543 (Uniprot-TrEMBL) | |
XRCC3 | Protein | O43542 (Uniprot-TrEMBL) | |
XRCC3 | Protein | O43542 (Uniprot-TrEMBL) | |
Zn2+ | Metabolite | CHEBI:29105 (ChEBI) | |
cleaved Holliday structure | R-NUL-83636 (Reactome) | ||
dNTP | Metabolite | CHEBI:16516 (ChEBI) | |
dsDNA with crossover | R-NUL-5686458 (Reactome) | ||
dsDNA with inter-SSA deletion | R-NUL-5686649 (Reactome) | ||
dsDNA | R-HSA-5649637 (Reactome) | ||
p-5S-BRCA1:p-2T-BARD1 | Complex | R-HSA-5683809 (Reactome) | |
p-5T-MDC1 | Protein | Q14676 (Uniprot-TrEMBL) | |
p-MRN | Complex | R-HSA-5682166 (Reactome) | |
p-RPA heterotrimer | Complex | R-HSA-5685169 (Reactome) | |
p-S102-WHSC1 | Protein | O96028 (Uniprot-TrEMBL) | |
p-S1981,Ac-K3016-ATM | Protein | Q13315 (Uniprot-TrEMBL) | |
p-S1981,Ac-K3016-ATM | Protein | Q13315 (Uniprot-TrEMBL) | |
p-S25,S1778-TP53BP1 | Protein | Q12888 (Uniprot-TrEMBL) | |
p-S25,S1778-TP53BP1 | Protein | Q12888 (Uniprot-TrEMBL) | |
p-S317,S345-CHEK1 | Protein | O14757 (Uniprot-TrEMBL) | |
p-S327,T847,T859-RBBP8 | Protein | Q99708 (Uniprot-TrEMBL) | |
p-S327,T847,T859-RBBP8 homotetramer | Complex | R-HSA-5684137 (Reactome) | |
p-S327,T847-RBBP8 | Protein | Q99708 (Uniprot-TrEMBL) | |
p-S33-RPA2 | Protein | P15927 (Uniprot-TrEMBL) | |
p-S343-NBN | Protein | O60934 (Uniprot-TrEMBL) | |
p-S406-FAM175A | Protein | Q6UWZ7 (Uniprot-TrEMBL) | |
p-S406-FAM175A | Protein | Q6UWZ7 (Uniprot-TrEMBL) | |
p-S456-ABL1 | Protein | P00519 (Uniprot-TrEMBL) | |
p-S988,S1387,S1423,S1524,S1547-BRCA1 | Protein | P38398 (Uniprot-TrEMBL) | |
p-S990,Ac-K1249-BRIP1 | Protein | Q9BX63 (Uniprot-TrEMBL) | |
p-S990,Ac-K1249-BRIP1 | Protein | Q9BX63 (Uniprot-TrEMBL) | |
p-T160-CDK2 | Protein | P24941 (Uniprot-TrEMBL) | |
p-T309-RAD51 | Protein | Q06609 (Uniprot-TrEMBL) | |
p-T309-RAD51 | Protein | Q06609 (Uniprot-TrEMBL) | |
p-T3387-BRCA2 | Protein | P51587 (Uniprot-TrEMBL) | |
p-T3387-BRCA2:p-T309-RAD51 complex | Complex | R-HSA-5693545 (Reactome) | |
p-T3387-BRCA2 | Protein | P51587 (Uniprot-TrEMBL) | |
p-T4827,SUMO1-HERC2 | Protein | O95714 (Uniprot-TrEMBL) | |
p-T714,T734-BARD1 | Protein | Q99728 (Uniprot-TrEMBL) | |
p-T916,S945-CLSPN | Protein | Q9HAW4 (Uniprot-TrEMBL) | |
p-T916,S945-CLSPN | Protein | Q9HAW4 (Uniprot-TrEMBL) | |
p-Y104-RAD52 heptamer | Complex | R-HSA-5686589 (Reactome) | |
p-Y104-RAD52 | Protein | P43351 (Uniprot-TrEMBL) | |
p-Y104-RAD52:p-RPA:ATR:ATRIP: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 | Complex | R-HSA-5693547 (Reactome) | |
ss-gap-reannealed DNA | R-NUL-84009 (Reactome) | ||
ubiquitin | Complex | R-HSA-68524 (Reactome) |
Annotated Interactions
View all... |
Source | Target | Type | Database reference | Comment |
---|---|---|---|---|
(SLX1A:SLX4:MUS81:EME1,EME2),GEN1 | mim-catalysis | R-HSA-5693584 (Reactome) | ||
2'-O-acetyl-ADP-ribose | Arrow | R-HSA-5685953 (Reactome) | ||
3'
overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-T309-RAD51:p-T3387-BRCA2:BCDX2 complex | Arrow | R-HSA-5685341 (Reactome) | ||
3'
overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-T309-RAD51:p-T3387-BRCA2:BCDX2 complex | R-HSA-5693620 (Reactome) | |||
3'
overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-T309-RAD51:p-T3387-BRCA2 | Arrow | R-HSA-5693561 (Reactome) | ||
3'
overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-T309-RAD51:p-T3387-BRCA2 | R-HSA-5685341 (Reactome) | |||
3'
overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1 | Arrow | R-HSA-5685994 (Reactome) | ||
3'
overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1 | R-HSA-5693542 (Reactome) | |||
3'
short overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1 | Arrow | R-HSA-5685985 (Reactome) | ||
3'
short overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1 | R-HSA-5685994 (Reactome) | |||
3'
short overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1 | mim-catalysis | R-HSA-5685994 (Reactome) | ||
3'
short overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex | Arrow | R-HSA-5693608 (Reactome) | ||
3'
short overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex | R-HSA-5685985 (Reactome) | |||
ADP | Arrow | R-HSA-5684096 (Reactome) | ||
ADP | Arrow | R-HSA-5684140 (Reactome) | ||
ADP | Arrow | R-HSA-5684887 (Reactome) | ||
ADP | Arrow | R-HSA-5685156 (Reactome) | ||
ADP | Arrow | R-HSA-5685230 (Reactome) | ||
ADP | Arrow | R-HSA-5685242 (Reactome) | ||
ADP | Arrow | R-HSA-5686410 (Reactome) | ||
ADP | Arrow | R-HSA-5686587 (Reactome) | ||
ADP | Arrow | R-HSA-5693589 (Reactome) | ||
ATP | R-HSA-5684096 (Reactome) | |||
ATP | R-HSA-5684140 (Reactome) | |||
ATP | R-HSA-5684887 (Reactome) | |||
ATP | R-HSA-5685156 (Reactome) | |||
ATP | R-HSA-5685230 (Reactome) | |||
ATP | R-HSA-5685242 (Reactome) | |||
ATP | R-HSA-5686410 (Reactome) | |||
ATP | R-HSA-5686587 (Reactome) | |||
ATP | R-HSA-5693589 (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 | Arrow | R-HSA-5685011 (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 | R-HSA-5685156 (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-catalysis | R-HSA-5685156 (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 | Arrow | R-HSA-5684875 (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 | R-HSA-5685011 (Reactome) | |||
ATR:ATRIP:p-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:TIMELESS:TIPIN:p-T916,S945-CLSPN:CHEK1 | Arrow | R-HSA-5684882 (Reactome) | ||
ATR:ATRIP:p-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:TIMELESS:TIPIN:p-T916,S945-CLSPN:CHEK1 | R-HSA-5684887 (Reactome) | |||
ATR:ATRIP:p-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:TIMELESS:TIPIN:p-T916,S945-CLSPN:CHEK1 | mim-catalysis | R-HSA-5684887 (Reactome) | ||
ATR:ATRIP:p-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 | Arrow | R-HSA-5684887 (Reactome) | ||
ATR:ATRIP:p-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 | Arrow | R-HSA-5685156 (Reactome) | ||
ATR:ATRIP:p-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 | R-HSA-5684882 (Reactome) | |||
ATR:ATRIP:p-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 | R-HSA-5693561 (Reactome) | |||
ATR:ATRIP:p-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 | R-HSA-5693580 (Reactome) | |||
ATR:ATRIP | Arrow | R-HSA-5686657 (Reactome) | ||
ATR:ATRIP | Arrow | R-HSA-5693561 (Reactome) | ||
ATR:ATRIP | R-HSA-5684875 (Reactome) | |||
Ac-K432,K526,K604-RBBP8 homotetramer | R-HSA-5685953 (Reactome) | |||
BABAM1 | Arrow | R-HSA-5684071 (Reactome) | ||
BCDX2 complex | Arrow | R-HSA-5685318 (Reactome) | ||
BCDX2 complex | Arrow | R-HSA-5686410 (Reactome) | ||
BCDX2 complex | Arrow | R-HSA-5686469 (Reactome) | ||
BCDX2 complex | Arrow | R-HSA-5686483 (Reactome) | ||
BCDX2 complex | Arrow | R-HSA-5693589 (Reactome) | ||
BCDX2 complex | R-HSA-5685341 (Reactome) | |||
BLM:TOP3A:RMI1:RMI2:SPIDR | Arrow | R-HSA-5686398 (Reactome) | ||
BLM:TOP3A:RMI1:RMI2:SPIDR | mim-catalysis | R-HSA-5686410 (Reactome) | ||
BLM:TOP3A:RMI1:RMI2 | R-HSA-5686398 (Reactome) | |||
BRCA2 | R-HSA-5685242 (Reactome) | |||
BRCC3 | Arrow | R-HSA-5684071 (Reactome) | ||
BRE | Arrow | R-HSA-5684071 (Reactome) | ||
CCNA:p-T160-CDK2 | Arrow | R-HSA-5684096 (Reactome) | ||
CCNA:p-T160-CDK2 | R-HSA-5684081 (Reactome) | |||
CHEK1 | R-HSA-5684882 (Reactome) | |||
CX3 complex | Arrow | R-HSA-5685319 (Reactome) | ||
CX3 complex | Arrow | R-HSA-5686410 (Reactome) | ||
CX3 complex | Arrow | R-HSA-5686469 (Reactome) | ||
CX3 complex | Arrow | R-HSA-5686483 (Reactome) | ||
CX3 complex | Arrow | R-HSA-5693589 (Reactome) | ||
CX3 complex | R-HSA-5685838 (Reactome) | |||
Cleaved D-Loop:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | Arrow | R-HSA-5686440 (Reactome) | ||
Cleaved D-Loop:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | R-HSA-5686469 (Reactome) | |||
Cleaved
Holliday Junction:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | Arrow | R-HSA-5693584 (Reactome) | ||
Cleaved
Holliday Junction:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | R-HSA-5686483 (Reactome) | |||
D-Loop:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | Arrow | R-HSA-5685838 (Reactome) | ||
D-Loop:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | R-HSA-5693593 (Reactome) | |||
D-Loop:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1 | Arrow | R-HSA-5693620 (Reactome) | ||
D-Loop:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1 | R-HSA-5685838 (Reactome) | |||
DNA
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:SUMO2:K1840,p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-5S,2T-BRCA1-A complex | Arrow | R-HSA-5684052 (Reactome) | ||
DNA
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:SUMO2:K1840,p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-5S,2T-BRCA1-A complex | R-HSA-5684071 (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-5S,2T-BRCA1-A complex | R-HSA-5684052 (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-5S,2T-BRCA1-A complex | mim-catalysis | R-HSA-5684052 (Reactome) | ||
DNA DSB:p-MRN:p-S1981,Ac-K3016-ATM:KAT5 | Arrow | R-HSA-5684071 (Reactome) | ||
DNA DSB:p-MRN:p-S1981,Ac-K3016-ATM:KAT5 | R-HSA-5684081 (Reactome) | |||
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:CCNA:p-T160-CDK2:RBBP8 | Arrow | R-HSA-5684081 (Reactome) | ||
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:CCNA:p-T160-CDK2:RBBP8 | R-HSA-5684096 (Reactome) | |||
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:CCNA:p-T160-CDK2:RBBP8 | mim-catalysis | R-HSA-5684096 (Reactome) | ||
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-BRCA1-C complex | Arrow | R-HSA-5684108 (Reactome) | ||
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-BRCA1-C complex | R-HSA-5693608 (Reactome) | |||
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-BRCA1-C complex | mim-catalysis | R-HSA-5693608 (Reactome) | ||
DNA DSBs:p-MRN:p-S327,T847,T859-RBBP8:p-S1981,Ac-K3016-ATM:KAT5 | Arrow | R-HSA-5684140 (Reactome) | ||
DNA DSBs:p-MRN:p-S327,T847,T859-RBBP8:p-S1981,Ac-K3016-ATM:KAT5 | R-HSA-5684108 (Reactome) | |||
DNA DSBs:p-MRN:p-S327,T847-RBBP8:p-S1981,Ac-K3016-ATM:KAT5 | Arrow | R-HSA-5684096 (Reactome) | ||
DNA DSBs:p-MRN:p-S327,T847-RBBP8:p-S1981,Ac-K3016-ATM:KAT5 | R-HSA-5684140 (Reactome) | |||
DNA DSBs:p-MRN:p-S327,T847-RBBP8:p-S1981,Ac-K3016-ATM:KAT5 | mim-catalysis | R-HSA-5684140 (Reactome) | ||
EME1,EME2 | R-HSA-5686430 (Reactome) | |||
ERCC1:ERCC4 | mim-catalysis | R-HSA-5686657 (Reactome) | ||
EXO1,DNA2:BLM,WRN | Arrow | R-HSA-5686410 (Reactome) | ||
EXO1,DNA2:BLM,WRN | Arrow | R-HSA-5686469 (Reactome) | ||
EXO1,DNA2:BLM,WRN | Arrow | R-HSA-5686483 (Reactome) | ||
EXO1,DNA2:BLM,WRN | Arrow | R-HSA-5686657 (Reactome) | ||
EXO1,DNA2:BLM,WRN | Arrow | R-HSA-5693589 (Reactome) | ||
EXO1,DNA2:BLM,WRN | R-HSA-5685985 (Reactome) | |||
Extended D-Loop:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | Arrow | R-HSA-5693593 (Reactome) | ||
Extended D-Loop:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | R-HSA-5686440 (Reactome) | |||
Extended D-Loop:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | R-HSA-5693539 (Reactome) | |||
Extended D-Loop:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | R-HSA-5693589 (Reactome) | |||
Flap | Arrow | R-HSA-5686657 (Reactome) | ||
H2O | R-HSA-5685994 (Reactome) | |||
H2O | R-HSA-5686410 (Reactome) | |||
H2O | R-HSA-5687758 (Reactome) | |||
H2O | R-HSA-5693589 (Reactome) | |||
H2O | R-HSA-5693608 (Reactome) | |||
Holliday Junction:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | Arrow | R-HSA-5693539 (Reactome) | ||
Holliday Junction:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | R-HSA-5686410 (Reactome) | |||
Holliday Junction:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-BRCA1-C complex:PALB2:p-T3387-BRCA2:p-T309-RAD51:RAD51AP1:CX3 complex | R-HSA-5693584 (Reactome) | |||
K48PolyUb:SUMO2:K1840,p-5T-MDC1 dimer | Arrow | R-HSA-5684071 (Reactome) | ||
K63PolyUb:K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome | Arrow | R-HSA-5684071 (Reactome) | ||
KAT5 | Arrow | R-HSA-5686410 (Reactome) | ||
KAT5 | Arrow | R-HSA-5686469 (Reactome) | ||
KAT5 | Arrow | R-HSA-5686483 (Reactome) | ||
KAT5 | Arrow | R-HSA-5686657 (Reactome) | ||
KAT5 | Arrow | R-HSA-5693589 (Reactome) | ||
MUS81:EME1,EME2 | Arrow | R-HSA-5686430 (Reactome) | ||
MUS81:EME1,EME2 | R-HSA-5686475 (Reactome) | |||
MUS81:EME1,EME2 | mim-catalysis | R-HSA-5686440 (Reactome) | ||
MUS81 | R-HSA-5686430 (Reactome) | |||
NAD+ | R-HSA-5685953 (Reactome) | |||
NAM | Arrow | R-HSA-5685953 (Reactome) | ||
PALB2 | Arrow | R-HSA-5686410 (Reactome) | ||
PALB2 | Arrow | R-HSA-5686469 (Reactome) | ||
PALB2 | Arrow | R-HSA-5686483 (Reactome) | ||
PALB2 | Arrow | R-HSA-5693589 (Reactome) | ||
PALB2 | R-HSA-5693620 (Reactome) | |||
PCNA:POLD,POLE,POLH,POLK:RPA:RFC | mim-catalysis | R-HSA-5693593 (Reactome) | ||
PIAS4 | Arrow | R-HSA-5684071 (Reactome) | ||
PPP4C:PPP4R2 | mim-catalysis | R-HSA-5687758 (Reactome) | ||
PPi | Arrow | R-HSA-5693593 (Reactome) | ||
Pi | Arrow | R-HSA-5686410 (Reactome) | ||
Pi | Arrow | R-HSA-5687758 (Reactome) | ||
Pi | Arrow | R-HSA-5693589 (Reactome) | ||
R-HSA-5684052 (Reactome) | PIAS4 SUMOylates MDC1 at lysine residue K1840. The exact timing and regulation of this modification is not known (Luo et al. 2012, Yin et al. 2012). | |||
R-HSA-5684071 (Reactome) | SUMOylation of MDC1 by PIAS4 creates a docking site for RNF4, an E3 ubiquitin ligase. RNF4 binds to MDC1 specifically when SUMO2 is attached to lysine K1840 of MDC1. RNF4 polyubiquitinates MDC1 through ubiquitin lysine residue K48 cross-linking. RNF4-mediated ubiquitination targets MDC1 for degradation and causes dissociation of MDC1-bound proteins from DNA double strand breaks (DSBs). While additional regulation steps may be involved, the activity of RNF4 is necessary for the initiation of resection of DNA ends at DSBs and progression of homologous recombination (Luo et al. 2012, Yin et al. 2012, Galanty et al. 2012). | |||
R-HSA-5684081 (Reactome) | In the S/G2 phase of the cell cycle, CDK2:CCNA (CDK2:cyclin A) complex and CtIP (RBBP8) are recruited to DNA double strand breaks (DSBs) by the MRN complex. RBBP8 interacts with NBN (NBS1) and RAD50 subunits, while CDK2:CCNA interacts with the MRE11A subunit of the complex (Buis et al. 2012). RBBP8 functions as a homotetramer (Davies et al. 2015). | |||
R-HSA-5684096 (Reactome) | CDK2, in complex with cyclin A (CCNA), phosphorylates RBBP8 (CtIP) on serine residue S327 and threonine residue T847. Residue T847 is conserved in the yeast ortholog of CtIP, Sae2, and phosphorylation of T847 increases CtIP activity in DNA end resection. Serine S327 phosphorylation enables CtIP to bind BRCA1 (Buis et al. 2012). | |||
R-HSA-5684108 (Reactome) | BRCA1:BARD1 complex binds RBBP8 (CtIP) phosphorylated by CDK2 at DNA double strand breaks (DSBs), thus forming the so-called BRCA1-C complex. As active CDK2 in complex with CCNA (cyclin A) exists only in the S and G2 phases of the cell cycle, this limits the formation of BRCA1 complex with RBBP8 and the consequent initiation of homologous recombination to S and G2 phases, when the genome is duplicated and sister chromatids are available (Chen et al. 2008, Yun and Hiom 2009). Dissociation of the BRCA1-A complex is necessary for BRCA1 to be able to bind RBBP8 (Coleman and Greenberg 2011). Phosphorylation of BRCA1 by CHEK2 also contributes to the initiation of homologous recombination, with this phosphorylation similarly serving as a molecular clock (Parameswaran et al. 2015). | |||
R-HSA-5684140 (Reactome) | CDK2-mediated phosphorylation of RBBP8 (CtIP) triggers ATM-mediated phosphorylation of RBBP8 on several ATM consensus SQ/TQ sites. The ATM phosphorylation site at threonine residue T859 of RBBP8 is evolutionarily conserved and seems to be particularly important for the RBBP8-promoted resection of DNA double strand break (DSB) ends (Wang et al. 2013). | |||
R-HSA-5684875 (Reactome) | ATR (ATM- and rad3-related) kinase is an essential checkpoint factor in human cells constitutively associated with ATRIP (ATR-interacting protein). The ATR:ATRIP complex binds RPA complex (RPA1:RPA2:RPA3) associated with ssDNA at resected DNA double strand breaks (DSBs). Complex formation is primarily mediated by physical interaction between ATRIP and RPA1 (Zou and Elledge 2003, Jazayeri et al. 2006). | |||
R-HSA-5684882 (Reactome) | The recruitment of CHEK1 (CHK1) to resected DNA double strand breaks (DSBs) and activation by ATR-mediated phosphorylation requires the presence of CLSPN (claspin) and TIMELESS:TIPIN protein complex. TIPIN simultaneously interacts with the RPA2 subunit of the RPA complex and CLSPN, allowing CLSPN to stably associate with resected DNA DSBs (Kemp et al. 2010). Phosphorylation of CLSPN at threonine T916 and serine S945 is needed for CHEK1 binding (Kumagai et al. 2003, Clarke and Clarke 2005). CLSPN phosphorylation at these sites is independent of CHEK1 (Bennett et al. 2008). Casein kinase 1 (CK1) was proposed as a kinase responsible for CLSPN phosphorylation (Meng et al. 2011) but the exact mechanism of this modification has not been established. ATR-mediated phosphorylation of RAD17 on serine residues S635 and S645 is implicated in CLSPN recruitment to resected DNA DSBs and CLSPN phosphorylation (Wang et al. 2006). Also, phosphorylation of the RPA2 subunit of the RPA complex positively contributes to CHEK1 activation (Liu et al. 2012). | |||
R-HSA-5684887 (Reactome) | CHEK1 (Chk1) is a checkpoint kinase activated during genotoxic stress. CHEK1 activation at resected DNA double strand breaks (DSBs) involves ATR-mediated phosphorylation of CHEK1 serine residues S317 and S345 in the presence of claspin (CLSPN), TOPBP1, RAD17:RFC complex, RAD9:HUS1:RAD1 complex, TIMELESS:TIPIN complex, RPA complex and RHNO1 (Liu et al. 2000, Zhao and Piwnica-Worms 2001, Kumagai and Dunphy 2003, Sorensen et al. 2004, Wang et al. 2006, Kemp et al. 2010, Cotta-Ramusino et al. 2011, Liu et al. 2012). Following phosphorylation, CHEK1 dissociates from chromatin and phosphorylates target proteins involved in S/G2 checkpoint activation and/or homologous recombination repair (Smits et al. 2006). CLSPN needs to interact with chromatin only transiently in order to facilitate CHEK1 activation (Lee et al. 2005). | |||
R-HSA-5685011 (Reactome) | ATR:ATRIP complex is recruited to resected DNA double strand breaks (DSBs) via interaction with the RPA complex that coats single strand DNA (ssDNA) 3'-overhangs, but this is not sufficient for ATR to become catalytically active. ATR kinase activity requires the presence of the RAD17:RFC complex, RAD9:HUS1:RAD1 (9-1-1) complex and TOPBP1. RAD17:RFC loads RAD9:HUS1:RAD1 onto junctions of single strand and double strand DNA (ssDNA-dsDNA junctions), present at resected DNA DSBs (Bermudez et al. 2003, reviewed by Sancar et al. 2004). TOPBP1 binds the C-terminal tail of RAD9, and is thus brought in the proximity of ATR, where it can activate it (Kumagai et al. 2006, Delacroix et al. 2007). The interaction of TOPBP1 and RBBP8 (CtIP) also contributes to TOPBP1 loading (Ramirez-Lugo et al. 2011). Phosphorylation of ATR at threonine residue T1989 may create a binding site for the BRCT domains of TOPBP1 (Liu et al. 2011). It is not clear whether T1989 of ATR is phosphorylated through autophosphorylation (Liu et al. 2011), as it does not conform to the SQ/TQ consensus, or by another kinase (Liu et al. 2013). RHNO1 (RHINO) protein simultaneously binds RAD9:HUS1:RAD1 complex and TOPBP1 and is required for the full catalytic activation of ATR (Cotta-Ramusino et al. 2011). | |||
R-HSA-5685156 (Reactome) | Activated ATR phosphorylates the RPA2 subunit of the RPA complex on serine residue S33. Phosphorylation of RPA2 at S33 likely stimulates additional RPA2 phosphorylation on CDK sites (S23 and S29) and DNA-PKcs (PRKDC) sites (S4, S8 and S21). DNA damage-regulated phosphorylation of RPA2 plays an important role in the progression of homologous recombination-directed repair of DNA double strand breaks (DSBs) (Anantha et al. 2007, Liu et al. 2012, Murphy et al. 2014) | |||
R-HSA-5685230 (Reactome) | Activated CHEK1 phosphorylates RAD51 on threonine residue T309, which is necessary for RAD51 association with chromatin (Sorensen et al. 2005). | |||
R-HSA-5685242 (Reactome) | CHEK1 phosphorylates BRCA2 on threonine residue T3887, in the C-terminal region of BRCA2. CHEK1-mediated BRCA2 phosphorylation, as well as CHEK1 mediated RAD51 phosphorylation, promotes the association of BRCA2 with RAD51 (Bahassi et al. 2008). | |||
R-HSA-5685318 (Reactome) | RAD51 paralogs RAD51B, RAD51C, RAD51D and XRCC2 form a complex named BCDX2 with 1:1:1:1 stoichiometry. In this complex, RAD51B directly interacts with RAD51C, which interacts with RAD51D, which interacts with XRCC2 (Masson et al. 2001, Chun et al. 2013). | |||
R-HSA-5685319 (Reactome) | RAD51 paralogs RAD51C and XRCC3 form the CX3 complex with 1:1 stoichiometry (Masson et al. 2001, Chun et al. 2013). | |||
R-HSA-5685341 (Reactome) | The BCDX2 complex, composed of RAD51 paralogs RAD51B, RAD51C, RAD51D and XRCC2, preferentially binds at the ends of 3' overhanging ssDNA created by resection of DNA double strand breaks (DSBs). The BCDX2 complex stabilizes nucleoprotein filaments formed by BRCA2-mediated RAD51 loading onto ssDNA (Masson et al. 2001, Chun et al. 2013). The BCDX2 complex may act by inhibiting displacement of RAD51 by BLM helicase (Amunugama et al. 2013). | |||
R-HSA-5685838 (Reactome) | The CX3 complex, composed of RAD51 paralogs RAD51C and XRCC3 (Masson, Tarsounas et al. 2001), binds homologous recombination repair sites at a later time point than the BCDX2 complex (Chun et al. 2013). Both RAD51C and XRCC3 can directly interact with PALB2 (Park et al. 2014). CX3 complexes, as well as BCDX2 complexes, multimerize into ring like structures with a central cavity (Masson, Stasiak et al. 2001, Compton et al. 2010). The CX3 complex may be involved in the resolution of Holliday junctions (Liu et al. 2004, Liu et al. 2007). | |||
R-HSA-5685953 (Reactome) | RBBP8 (CtIP) is constitutively acetylated in the absence of DNA damage on lysine residues K432, K526 and K604, and perhaps other lysines. DNA damage, through an unknown mechanism, triggers deacetylation of RBBP8 by SIRT6 protein lysine deacetylase. SIRT6-mediated deacetylation of RBBP8 is necessary for RBBP8-promoted resection of DNA double strand breaks (DSBs) (Kaidi et al. 2010). | |||
R-HSA-5685985 (Reactome) | After the initial resection of DNA double strand breaks (DSBs) by MRE11A and RBBP8 (CtIP), which creates short 3' ssDNA overhangs, a DNA exonuclease EXO1 or a DNA endonuclease DNA2 is recruited to perform long-range resection of DNA DSBs. The redundant function of EXO1 and DNA2 in resection of DNA DSBs is conserved in yeast (Zhu et al. 2008). BLM, the Bloom syndrome helicase, acts as an activator of DNA2 catalytic activity (Nimonkar et al. 2011) and increases affinity of EXO1 for DNA ends (Nimonkar et al. 2008). BLM directly interacts with the MRN complex, which can assist recruitment of either DNA2 or EXO1 to DNA DSBs (Nimonkar et al. 2011). EXO1 can also be recruited to DNA DSBs through its interaction with RBBP8 (CtIP) (Eid et al. 2010, Nimonkar et al. 2011). Another DNA helicase, WRN (Werner syndrome helicase) can function redundantly with BLM to facilitate/activate EXO1- or DNA2-mediated long range resection of DNA DSBs (Sturzenegger et al. 2014). A DNA helicase BRIP1 (also known as BACH1 or FANCJ) is recruited to DNA DSBs through its interaction with BRCA1 (Cantor et al. 2001) and BLM (Suhasini et al. 2011, Suhasini and Brosh 2012). BRIP1 promotes DNA end processing events that stimulate recruitment of the RPA complex and RAD51 (Xie et al. 2012). The interaction with BRCA1 requires BRIP1 to be phosphorylated on serine residue S990 in a cell cycle-dependent manner (Yu et al. 2003). BRIP1 also has to be acetylated on lysine residue K1249 to be functional (Xie et al. 2012). | |||
R-HSA-5685994 (Reactome) | DNA nucleases EXO1 and DNA2 function redundantly in yeast (Zhu et al. 2008) and humans (Nimonkar et al. 2011) in long-range resection of DNA double strand breaks (DSBs). Both DNA nucleases act after short 3' ssDNA overhangs are created by the initial resection of DNA DSBs mediated by MRE11A and RBBP8 (CtIP). The roles of BLM (Bloom syndrome helicase) and WRN (Werner syndrome helicase) in facilitation of EXO1- or DNA2-mediated resection of DNA DSBs are also redundant. EXO1 possesses an intrinsic 5'->3' exonuclease activity. The ATPase activity of BLM DNA helicase is not required for EXO1 catalytic activity, but BLM increases the affinity of EXO1 for DNA ends (Nimonkar et al. 2008). WRN can also positively affect EXO1 exonuclease activity, although the mechanism is not clear (Sturzenegger et al. 2014). The DNA endonuclease DNA2 has to form a complex with either BLM (Nimonkar et al. 2011) or WRN (Sturzenegger et al. 2014) in order to perform a 5'->3' directed resection of DNA DSBs. BLM forms an evolutionarily conserved complex with TOP3A, RMI1 and RMI2, known as the STR complex in yeast (Zhu et al. 2008) and the BTB or BTRR complex in humans. The entire BTRR complex participates in the activation of DNA2-mediated resection of DNA DSBs (Sturzenegger et al. 2014). While ATR signaling may be detectable in the absence of long-range resection of DNA DSBs by EXO1 or DNA2 (Eid et al. 2010), EXO1 or DNA2 activity may be necessary to achieve biologically meaningful level of ATR activation (Gravel et al. 2008). BRIP1 (BACH1, FANCJ) is a DNA helicase recruited to DNA DSBs by interaction with BRCA1 (Cantor et al. 2001) and BLM (Suhasini et al. 2011). BRIP1 is necessary for BRCA1-mediated homology-directed repair of DNA DSBs, and BRIP1 loss-of-function mutations are found in familial breast cancer (Cantor et al. 2001, Litman et al. 2005). The exact role of BRIP1 in DNA repair is not completely clear. BRIP1 is needed for the successful formation of RPA foci and, subsequently, RAD51 foci (Xie et al. 2012). The available evidence suggest that it cooperates with BLM in unwinding of DNA DSBs during resection (Suhasini et al. 2011, Sarkies et al. 2012), and may be especially important for unwinding of DNA that contains oxidative damage (Suhasini et al. 2009). | |||
R-HSA-5686398 (Reactome) | SPIDR binds the BTRR complex (BLM:TOP3A:RMI1:RMI2) through a direct interaction with BLM. SPIDR also interacts with RAD51, thereby connecting the BTRR complex with Holliday Junctions (Wan et al. 2013). | |||
R-HSA-5686410 (Reactome) | The BTRR complex, composed of BLM, TOP3A, RMI1 and RMI2, dissolves double Holliday junctions by disentangling hemicatenane intermediates (Bocquet et al. 2014). This results in non-crossover products, where no exchange of genetic material happens between the sister chromatid that served as a template for the DNA repair synthesis and the repaired DNA duplex. SPIDR serves as a scaffold that connects the BTRR complex with the double Holliday junction through its simultaneous interaction with RAD51-coated DNA strands of the Holliday junction and BLM. SPIDR is needed for BTRR-mediated prevention of cross-over between sister chromatids (Wan et al. 2013). | |||
R-HSA-5686430 (Reactome) | MUS81 binds EME1 (MMS4) to form an evolutionarily conserved endonuclease complex involved in processing of aberrant replication intermediates and the cleavage of homologous recombination intermediates (Ciccia et al. 2003, Ogrunc and Sancar 2003). MUS81 can also form an endonuclease complex with EME2. EME2 is 40% identical to EME1 at the amino acid level and the MUS81:EME2 complex likely functions in a similar way to the MUS81:EME1 complex (Ciccia et al. 2007). | |||
R-HSA-5686440 (Reactome) | The complex of MUS81 and EME1 or EME2 acts as an endonuclease and processes D-loops by cleaving the sister chromatid strand complementary to the invading strand at the junction point. MUS81:EME2 complex has a higher catalytic activity than MUS81:EME1 complex and, in vitro, cleaves D-loops at several other sites in addition to the junction point (Osman et al. 2003, Pepe and West 2014). The yeast Mus81:Eme1 (Mus81:Mms4) complex also acts on D-loops (Schwartz et al. 2012). | |||
R-HSA-5686469 (Reactome) | Based on studies in yeast, D-loop cleavage by MUS81 in complex with EME1 or EME2 always produces crossovers between sister chromatids (Osman et al. 2003). The identity of the DNA polymerase(s) and ligase(s) that complete DNA repair synthesis and ligation after MUS81:EME1 or MUS81:EME2 cleavage of D-loops has not been determined. | |||
R-HSA-5686475 (Reactome) | SLX1A (SLX1) and SLX4 constitutively form a heterodimeric endonucleolytic complex that possesses a robust Holliday junction resolvase activity (Fekairi et al. 2009). SLX1A:SLX4 can form a complex with the MUS81:EME1 (and likely MUS81:EME2) complex, named SLX-MUS, through direct interaction of SLX4 with MUS81 (Fekairi et al. 2009, Wyatt et al. 2013). SLX-MUS is a more efficient and coordinated resolvase of Holliday junctions than SLX1A:SLX4 or MUS81:EME1,EME2 (Wyatt et al. 2013). | |||
R-HSA-5686483 (Reactome) | The identity of DNA ligases that ligate DNA strands generated during cleavage of Holliday junctions by GEN1 or the SLX-MUS complex (composed of SLX1A:SLX4 heterodimer and MUS81:EME1 or possibly MUS81:EME2 heterodimer) is not known. The resolvase activity of GEN1 or SLX-MUS predominantly results in the generation of crossover products, with exchange of genetic material between sister chromatids (Wyatt et al. 2013). | |||
R-HSA-5686587 (Reactome) | ABL1 (c-ABL), activated by ATM-mediated phosphorylation in response to DNA double strand breaks (DSBs), phosphorylates RAD52 on tyrosine residue Y104, thus increasing the affinity of RAD52 heptamer for ssDNA and enhancing the efficiency of RAD52-mediated single strand annealing (SSA) (Honda et al. 2011). | |||
R-HSA-5686642 (Reactome) | RAD52 promotes annealing of 3' ssDNA overhangs at resected DNA double strand breaks (DSBs) through complementary regions. The complementarity between the two 3' ssDNA overhangs at resected DNA DSBs exists if 3' ssDNA overhangs contain direct repeats. While single strand annealing (SSA) requires significant homology between the annealed sequences it is nonetheless mutagenic. The parts of two 3' overhanging DNA single strands at resected DSBs that lie 3' to the annealed regions become displaced as flaps and subsequently excised. This results in the deletion (loss) of the DNA sequence lying between the two regions of homology used for SSA, as well as the deletion of one of the repeats used for annealing (Parsons et al. 2000, Van Dyck et al. 2001, Singleton et al. 2002, Stark et al. 2004, Mansour et al. 2008). | |||
R-HSA-5686657 (Reactome) | The endonuclease complex ERCC1:XPF (ERCC1:ERCC4) is recruited to single strand annealing (SSA) sites of DNA double strand break (DSB) repair through direct interaction between XPF (ERCC4) and RAD52 (Motycka et al. 2004). ERCC1:XPF cleaves the ssDNA flaps generated by displacement of non-complementary 3' parts of 3' ssDNA overhangs during RAD52-mediated annealing. The enzymatic activity of ERCC1:XPF is necessary for the completion of SSA (Motycka et al. 2004, Al-Minawi et al. 2008, Ahmad et al. 2008). | |||
R-HSA-5686663 (Reactome) | An unknown DNA ligase ligates single strand breaks (SSBs) remaining after RAD52-mediated single strand annealing (SSA) of resected DNA double strand breaks (DSBs) and cleavage of displaced flaps by ERCC1:XPF (ERCC1:ERCC4). The product of SSA is a double-strand DNA with a deletion of one complementary region (repeat) and the sequence lying between the two complementary regions used for SSA (inter-SSA deletion) (reviewed by Ciccia and Elledge 2010). | |||
R-HSA-5687758 (Reactome) | The protein serine/threonine phosphatase complex composed of a catalytic subunit PPP4C (PP4C) and a regulatory subunit PPP4R2 (PP4R2) dephosphorylates serine S33 of the RPA2 subunit of the RPA heterotrimer. By regulating the availability of unphosphorylated RPA2, PPP4C:PPP4R2 phosphatase regulates the progression of the homologous recombination repair of DNA double strand breaks and the duration of ATR checkpoint signaling (Lee et al. 2010). | |||
R-HSA-5693539 (Reactome) | Ligation of the crossed-strand intermediate results in the formation of double Holliday junctions with two crossovers. In humans, the identity of the ligase activity involved in this process is not known (reviewed by Ciccia and Elledge 2010). | |||
R-HSA-5693542 (Reactome) | Human replication protein A (RPA) is a single-stranded DNA (ssDNA) binding protein complex required for DNA replication, recombination, and repair. RPA is a stable heterotrimer consisting of subunits with molecular masses of 14, 32 and 70 kDa (p14, p32 and p70, respectively). Association of RPA with ssDNA is thought to contribute to both the protection and removal of secondary structure from single-stranded DNA (ssDNA) (McIlwraith et al. 2000). The RPA complexes coat 3'-ssDNA overhangs generated by RBBP8 (CtIP)-initiated long-range resection of DNA double strand breaks (DSBs) (Sartori et al. 2007, Chen et al. 2008). | |||
R-HSA-5693558 (Reactome) | After synthesis-dependent strand annealing (SDSA), the reannealed DNA molecule contains a single strand nick (SSB) in the newly synthesized strand, between the 3' end of the newly added stretch of nucleotides and the resected 5' end of the strand. In addition, the complementary strand contains a gap created by resection that was not filled during DNA repair synthesis. Additional DNA synthesis occurs to fill in this remaining single-strand gap present in the reannealed DNA duplex. SSBs between newly added stretches of nucleotides and resected 5' ends need to be closed by DNA ligases. The identity of DNA polymerase(s) and DNA ligase(s) involved in the completion of DNA double strand break repair through SDSA is not known. RTEL1 DNA helicase, which resolves D-loops in SDSA, binds PCNA and may promote DNA synthesis after reannealing (Vannier et al. 2013). DNA polymerase alpha is implicated in late steps of DNA repair synthesis (Levy et al. 2009), but other PCNA-bound DNA polymerases may also be involved. LIG1, as well as LIG3 in complex with XRCC1, may act to ligate SSBs (Fan et al. 2004, Mortusewicz et al. 2006, Mortusewicz et al. 2007, Puebla-Osorio et al. 2006). | |||
R-HSA-5693561 (Reactome) | BRCA2 and RAD51 interact directly through the highly conserved BRCT repeats in BRCA2 (Venkitaraman 2002). CHEK1-mediated phosphorylation of BRCA2 (at threonine residue T3387) and RAD51 (at threonine residue T309) facilitates their binding (Sorensen et al. 2005, Bahassi et al. 2008). One BRCA2 can bind up to six RAD51 molecules, thus playing an important role in RAD51 nucleation at the dsDNA-ssDNA junction created by resection of DNA double strand breaks (DSBs) (Liu et al. 2010, Thorslund et al. 2010, Jensen et al. 2010). After the nucleation step, additional RAD51 molecules bind the ssDNA and multimerize, forming RAD51 nucleoprotein filaments (Yang et al. 2005). BRCA2-mediated RAD51 loading displaces the RPA complex from 3' overhanging ssDNA at DSBs (Sugiyama et al. 1997, Jensen et al. 2010), presumably with other RPA-bound proteins, such as ATR:ATRIP and complexes involved in ATR catalytic activation. | |||
R-HSA-5693564 (Reactome) | RAD52 can simultaneously interact with RAD51 and RPA. The interaction with RAD51 may inhibit the formation of the invading RAD51 filament by sequestering RAD51 from RPA, thus promoting single strand annealing (SSA) instead of homologous recombination (Chen et al. 1999, Stark et al. 2004, Singleton et al. 2002, Mansour et al. 2008). The interaction of RAD51 and RAD52 is promoted by ABL1-mediated phosphorylation of both RAD51 and RAD52 (Chen et al. 1999, Van Dyck et al. 1999), which also increases RAD52 affinity for DNA (Honda et al. 2011). | |||
R-HSA-5693580 (Reactome) | RAD52 heptamers bind 3' overhanging ssDNA at resected DNA double strand breaks (DSBs) by simultaneously interacting with the DNA and the RPA complex. The conformation of the RAD52-ssDNA complex is thought to place the ssDNA on an exposed surface of the ring, in a configuration that may promote the DNA-DNA annealing of complementary DNA strands (Parsons et al. 2000). The interaction with RPA is necessary for RAD52-mediated homology driven repair (Park et al. 1996, Jackson et al. 2002). Phosphorylation of RAD52 at tyrosine residue Y104 by ABL1 in response to ATM signaling increases the affinity of RAD52 for DNA (Kitao et al. 2002, Cramer et al. 2008, Honda et al. 2011). Long range resection, which results in the activation of ATR/CHEK1 signaling, is needed for RAD52-mediated single strand annealing (SSA). RAD52 function may be promoted by a direct interaction with WRN helicase which participates in long-range resection of DNA DSBs (Baynton et al. 2003). | |||
R-HSA-5693584 (Reactome) | Holliday junctions are efficiently cleaved either by GEN1 endonuclease or the SLX-MUS complex, composed of the SLX1A:SLX4 heterodimer and the heterodimer of MUS81 and EME1 (or, possibly, EME2). Both SLX1A:SLX4 and MUS1:EME1,EME2 possess endonucleolytic activity and act in a coordinated fashion. SLX1A:SLX4 cleaves the double Holliday junction first, which is followed by MUS81:EME1 (or MUS81:EME2) mediated cleavage of the incised Holliday junction. Cleavage by both GEN1 and SLX-MUS predominantly leads to exchange of genetic material between sister chromatids, creating crossover products (Wyatt et al. 2013, Sarbajna et al. 2014). | |||
R-HSA-5693589 (Reactome) | Following repair synthesis, the extended D-loop strands may disassociate from their sister chromatid complements and reanneal with their original complementary strands. A DNA helicase RTEL1 disrupts preformed D-loops and promotes synthesis-dependent strand annealing, yielding non-crossover products and preventing excessive recombination between mitotic sister chromatids (Barber et al. 2008, Uringa et al. 2012). | |||
R-HSA-5693593 (Reactome) | Following branch migration, the invading 3' resected ssDNA end of the double-strand break (DSB) acts as a primer for repair DNA synthesis using the complementary strand of the invaded duplex as a template. The replicative DNA polymerases delta (POLD) and likely epsilon (POLE), as well as translesion synthesis (TLS) DNA polymerases eta (POLH) and kappa (POLK) in complex with PCNA, RFC and RPA are implicated in DNA repair synthesis and D-loop extension. While TLS polymerases increase the efficiency of homologous recombination-related DNA synthesis and can directly interact with D-loop proteins RAD51, PALB2 and BRCA2, it is likely that replicative DNA polymerases POLD and POLE, with their high processivity and fidelity, perform the major role in D-loop extension (McIlwraith et al. 2005, Sebesta et al. 2013, Pomerantz et al. 2013, Buisson et al. 2014). In addition, the presence of RAD51-translocases, homologous to yeast Rad54, that remove RAD51 from the 3' invading strand, may be necessary for the catalytic activity of POLD or POLE (Li et al. 2009, Li and Heyer 2009). | |||
R-HSA-5693608 (Reactome) | In order for repair of the DNA double-strand breaks to occur through homologous recombination or single strand annealing, the 5' ends of the break must first be resected to produce 3' overhanging single stranded DNA (ssDNA) that can subsequently invade homologous duplex DNA (e.g. in the sister chromatid) (Thompson et al. 2001, Kolpashchikov et al. 2001). The MRE11A component of the MRN complex possesses endonuclease activity (Trujillo et al. 1998, Hopfner et al. 2002) that is activated by binding of RBBP8 (CtIP) and BRCA1, in the presence of Mn2+ or Mg2+ ions (Sartori et al. 2007, Yun and Hiom 2009). | |||
R-HSA-5693620 (Reactome) | A D-loop structure is formed when complementary duplex DNA (sister chromatid arm) is progressively invaded by the RAD51 nucleoprotein filament, with base pairing of the invading ssDNA and the complementary sister chromatid DNA strand (Sung et al. 2003). PALB2 and RAD51AP1 synergistically stimulate RAD51 recombinase activity, thus enhancing RAD51-mediated strand exchange (branch migration) and promoting the formation of D-loop structures (synaptic complex assembly). PALB2 simultaneously interacts with RAD51, BRCA2 and RAD51AP1 (Modesti et al. 2007, Wiese et al. 2007, Buisson et al. 2010, Dray et al. 2010). The direct BRCA1 interaction with PALB2 helps to fine-tune the localization of BRCA2 and RAD51 at DNA double strand breaks (DSBs) (Zhang et al. 2009, Sy et al. 2009). | |||
R-HSA-75998 (Reactome) | RAD52 forms heptameric ring structure complexes (Stasiak et al. 2000, Kagawa et al. 2002, Lloyd et al. 2002, Singleton et al. 2002). | |||
RAD17:RFC | Arrow | R-HSA-5686657 (Reactome) | ||
RAD17:RFC | Arrow | R-HSA-5693561 (Reactome) | ||
RAD17:RFC | R-HSA-5685011 (Reactome) | |||
RAD51:p-Y104-RAD52:p-RPA:ATR:ATRIP: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 | Arrow | R-HSA-5693564 (Reactome) | ||
RAD51:p-Y104-RAD52:p-RPA:ATR:ATRIP: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 | R-HSA-5686642 (Reactome) | |||
RAD51:p-Y104-RAD52:p-RPA:ATR:ATRIP: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-catalysis | R-HSA-5686642 (Reactome) | ||
RAD51:p-Y104-RAD52:p-RPA:ATR:ATRIP:DNA DSBs with annealed 3' ssDNA overhangs and displaced flaps: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 | Arrow | R-HSA-5686642 (Reactome) | ||
RAD51:p-Y104-RAD52:p-RPA:ATR:ATRIP:DNA DSBs with annealed 3' ssDNA overhangs and displaced flaps: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 | R-HSA-5686657 (Reactome) | |||
RAD51AP1 | Arrow | R-HSA-5686410 (Reactome) | ||
RAD51AP1 | Arrow | R-HSA-5686469 (Reactome) | ||
RAD51AP1 | Arrow | R-HSA-5686483 (Reactome) | ||
RAD51AP1 | Arrow | R-HSA-5693589 (Reactome) | ||
RAD51AP1 | R-HSA-5693620 (Reactome) | |||
RAD51 | Arrow | R-HSA-5686657 (Reactome) | ||
RAD51B | R-HSA-5685318 (Reactome) | |||
RAD51C | R-HSA-5685318 (Reactome) | |||
RAD51C | R-HSA-5685319 (Reactome) | |||
RAD51D | R-HSA-5685318 (Reactome) | |||
RAD51 | R-HSA-5685230 (Reactome) | |||
RAD51 | R-HSA-5693564 (Reactome) | |||
RAD52 heptamer | Arrow | R-HSA-75998 (Reactome) | ||
RAD52 heptamer | R-HSA-5686587 (Reactome) | |||
RAD52 | R-HSA-75998 (Reactome) | |||
RAD9:HUS1:RAD1 | Arrow | R-HSA-5686657 (Reactome) | ||
RAD9:HUS1:RAD1 | Arrow | R-HSA-5693561 (Reactome) | ||
RAD9:HUS1:RAD1 | R-HSA-5685011 (Reactome) | |||
RBBP8 homotetramer | Arrow | R-HSA-5685953 (Reactome) | ||
RBBP8 homotetramer | R-HSA-5684081 (Reactome) | |||
RHNO1 | Arrow | R-HSA-5686657 (Reactome) | ||
RHNO1 | Arrow | R-HSA-5693561 (Reactome) | ||
RHNO1 | R-HSA-5685011 (Reactome) | |||
RNF168 | Arrow | R-HSA-5684071 (Reactome) | ||
RNF4 homodimer | mim-catalysis | R-HSA-5684071 (Reactome) | ||
RNF8:Zn2+ | Arrow | R-HSA-5684071 (Reactome) | ||
RPA heterotrimer | Arrow | R-HSA-5687758 (Reactome) | ||
RPA heterotrimer | R-HSA-5693542 (Reactome) | |||
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 | Arrow | R-HSA-5693542 (Reactome) | ||
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 | R-HSA-5684875 (Reactome) | |||
RTEL1 | mim-catalysis | R-HSA-5693589 (Reactome) | ||
SIRT6 | mim-catalysis | R-HSA-5685953 (Reactome) | ||
SLX1A:SLX4:MUS81:EME1,EME2 | Arrow | R-HSA-5686475 (Reactome) | ||
SLX1A:SLX4 | R-HSA-5686475 (Reactome) | |||
SPIDR | R-HSA-5686398 (Reactome) | |||
SSB-dsDNA with inter-SSA deletion | Arrow | R-HSA-5686657 (Reactome) | ||
SSB-dsDNA with inter-SSA deletion | R-HSA-5686663 (Reactome) | |||
SUMO1:p-T4827-HERC2 | Arrow | R-HSA-5684071 (Reactome) | ||
SUMO2:UBE2I | R-HSA-5684052 (Reactome) | |||
Sister Chromatid Arm with Crossover | Arrow | R-HSA-5686469 (Reactome) | ||
Sister Chromatid Arm with Crossover | Arrow | R-HSA-5686483 (Reactome) | ||
Sister Chromosomal Arm | Arrow | R-HSA-5686410 (Reactome) | ||
Sister Chromosomal Arm | Arrow | R-HSA-5693589 (Reactome) | ||
Sister Chromosomal Arm | R-HSA-5693620 (Reactome) | |||
TIMELESS:TIPIN | Arrow | R-HSA-5684887 (Reactome) | ||
TIMELESS:TIPIN | R-HSA-5684882 (Reactome) | |||
TOPBP1 | Arrow | R-HSA-5686657 (Reactome) | ||
TOPBP1 | Arrow | R-HSA-5693561 (Reactome) | ||
TOPBP1 | R-HSA-5685011 (Reactome) | |||
UBE2I | Arrow | R-HSA-5684052 (Reactome) | ||
UBE2N:UBE2V2 | Arrow | R-HSA-5684071 (Reactome) | ||
UIMC1 | Arrow | R-HSA-5684071 (Reactome) | ||
WHSC1 | Arrow | R-HSA-5684071 (Reactome) | ||
XRCC2 | R-HSA-5685318 (Reactome) | |||
XRCC3 | R-HSA-5685319 (Reactome) | |||
dNTP | Arrow | R-HSA-5685994 (Reactome) | ||
dNTP | Arrow | R-HSA-5693608 (Reactome) | ||
dNTP | R-HSA-5693593 (Reactome) | |||
dsDNA with crossover | Arrow | R-HSA-5686469 (Reactome) | ||
dsDNA with crossover | Arrow | R-HSA-5686483 (Reactome) | ||
dsDNA with inter-SSA deletion | Arrow | R-HSA-5686663 (Reactome) | ||
dsDNA | Arrow | R-HSA-5686410 (Reactome) | ||
dsDNA | Arrow | R-HSA-5693558 (Reactome) | ||
p-5S-BRCA1:p-2T-BARD1 | Arrow | R-HSA-5684071 (Reactome) | ||
p-5S-BRCA1:p-2T-BARD1 | Arrow | R-HSA-5686410 (Reactome) | ||
p-5S-BRCA1:p-2T-BARD1 | Arrow | R-HSA-5686469 (Reactome) | ||
p-5S-BRCA1:p-2T-BARD1 | Arrow | R-HSA-5686483 (Reactome) | ||
p-5S-BRCA1:p-2T-BARD1 | Arrow | R-HSA-5686657 (Reactome) | ||
p-5S-BRCA1:p-2T-BARD1 | Arrow | R-HSA-5693589 (Reactome) | ||
p-5S-BRCA1:p-2T-BARD1 | R-HSA-5684108 (Reactome) | |||
p-MRN | Arrow | R-HSA-5686410 (Reactome) | ||
p-MRN | Arrow | R-HSA-5686469 (Reactome) | ||
p-MRN | Arrow | R-HSA-5686483 (Reactome) | ||
p-MRN | Arrow | R-HSA-5686657 (Reactome) | ||
p-MRN | Arrow | R-HSA-5693589 (Reactome) | ||
p-RPA heterotrimer | Arrow | R-HSA-5686657 (Reactome) | ||
p-RPA heterotrimer | Arrow | R-HSA-5693561 (Reactome) | ||
p-RPA heterotrimer | R-HSA-5687758 (Reactome) | |||
p-S1981,Ac-K3016-ATM | Arrow | R-HSA-5686410 (Reactome) | ||
p-S1981,Ac-K3016-ATM | Arrow | R-HSA-5686469 (Reactome) | ||
p-S1981,Ac-K3016-ATM | Arrow | R-HSA-5686483 (Reactome) | ||
p-S1981,Ac-K3016-ATM | Arrow | R-HSA-5686657 (Reactome) | ||
p-S1981,Ac-K3016-ATM | Arrow | R-HSA-5693589 (Reactome) | ||
p-S25,S1778-TP53BP1 | Arrow | R-HSA-5684071 (Reactome) | ||
p-S317,S345-CHEK1 | Arrow | R-HSA-5684887 (Reactome) | ||
p-S317,S345-CHEK1 | mim-catalysis | R-HSA-5685230 (Reactome) | ||
p-S317,S345-CHEK1 | mim-catalysis | R-HSA-5685242 (Reactome) | ||
p-S327,T847,T859-RBBP8 homotetramer | Arrow | R-HSA-5686410 (Reactome) | ||
p-S327,T847,T859-RBBP8 homotetramer | Arrow | R-HSA-5686469 (Reactome) | ||
p-S327,T847,T859-RBBP8 homotetramer | Arrow | R-HSA-5686483 (Reactome) | ||
p-S327,T847,T859-RBBP8 homotetramer | Arrow | R-HSA-5686657 (Reactome) | ||
p-S327,T847,T859-RBBP8 homotetramer | Arrow | R-HSA-5693589 (Reactome) | ||
p-S406-FAM175A | Arrow | R-HSA-5684071 (Reactome) | ||
p-S456-ABL1 | mim-catalysis | R-HSA-5686587 (Reactome) | ||
p-S990,Ac-K1249-BRIP1 | Arrow | R-HSA-5686410 (Reactome) | ||
p-S990,Ac-K1249-BRIP1 | Arrow | R-HSA-5686483 (Reactome) | ||
p-S990,Ac-K1249-BRIP1 | Arrow | R-HSA-5686657 (Reactome) | ||
p-S990,Ac-K1249-BRIP1 | Arrow | R-HSA-5693589 (Reactome) | ||
p-S990,Ac-K1249-BRIP1 | R-HSA-5685985 (Reactome) | |||
p-T309-RAD51 | Arrow | R-HSA-5685230 (Reactome) | ||
p-T309-RAD51 | R-HSA-5693561 (Reactome) | |||
p-T3387-BRCA2:p-T309-RAD51 complex | Arrow | R-HSA-5686410 (Reactome) | ||
p-T3387-BRCA2:p-T309-RAD51 complex | Arrow | R-HSA-5686469 (Reactome) | ||
p-T3387-BRCA2:p-T309-RAD51 complex | Arrow | R-HSA-5686483 (Reactome) | ||
p-T3387-BRCA2:p-T309-RAD51 complex | Arrow | R-HSA-5693589 (Reactome) | ||
p-T3387-BRCA2 | Arrow | R-HSA-5685242 (Reactome) | ||
p-T3387-BRCA2 | R-HSA-5693561 (Reactome) | |||
p-T916,S945-CLSPN | Arrow | R-HSA-5684887 (Reactome) | ||
p-T916,S945-CLSPN | R-HSA-5684882 (Reactome) | |||
p-Y104-RAD52 heptamer | Arrow | R-HSA-5686587 (Reactome) | ||
p-Y104-RAD52 heptamer | Arrow | R-HSA-5686657 (Reactome) | ||
p-Y104-RAD52 heptamer | R-HSA-5693580 (Reactome) | |||
p-Y104-RAD52:p-RPA:ATR:ATRIP: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 | Arrow | R-HSA-5693580 (Reactome) | ||
p-Y104-RAD52:p-RPA:ATR:ATRIP: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 | R-HSA-5693564 (Reactome) | |||
ss-gap-reannealed DNA | Arrow | R-HSA-5693589 (Reactome) | ||
ss-gap-reannealed DNA | R-HSA-5693558 (Reactome) | |||
ubiquitin | R-HSA-5684071 (Reactome) |