DNA Double Strand Break Response (Homo sapiens)

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65756, 10, 20, 36, 45...113982718, 2313, 26, 56, 94, 114...3, 64235, 58, 78, 1085, 41, 47, 69, 76...67, 71, 80, 8723, 26, 56, 114, 12113, 34, 84, 94, 116101, 11937, 9817, 43, 73, 112331, 14, 11629, 106, 11078, 86, 119, 120, 12241, 59, 90, 91, 9310027, 8810071, 79, 10623, 56, 116432, 28, 6827, 31, 35, 74, 81...49, 1094, 53, 6231, 35, 44, 74, 9698, 10019, 2315, 16, 66, 12327, 63, 889816, 3856, 11675488, 34, 42, 107cytosolnucleoplasmDNADNADSBs: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:UIMC1:p-S406-FAM175ANBN HIST1H2BB HIST3H3 HIST1H2BM EYA1-4H2BFS MRE11A HIST3H3 HIST3H2BB p-S343-NBN Zn2+ HIST1H2BK p-S102-WHSC1 gamma-ray DNA double-strand break ends p-S1387,S1423,S1524,S1547-BRCA1 H2BFS KAT5 HIST1H2BD HIST1H2BH KAT5 KAT5 UBE2V2 HIST1H2BN BABAM1MDC1K63PolyUb-K14,K16,p-S140-H2AFX Zn2+ RNF8 p-T4827,SUMO1-HERC2 HIST1H2BD HIST3H2BB p-T4827,SUMO1-HERC2 RAD50 DNA double-strand break ends MRE11A p-5T-MDC1 Zn2+ HIST1H2BL HIST3H3 DNA double-strand break ends p-S25,S1778-TP53BP1 DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-NucleosomeADPHIST1H2BA HIST1H2BM p-S1981,Ac-K3016-ATM HIST1H2BM WHSC1HIST1H2BA HIST2H2BE p-S102-WHSC1 HIST1H2BJ KAT5 HIST1H2BN UIMC1 HIST3H2BB DNA double-strand break ends HIST1H2BH HIST1H2BD RAD50 HIST1H2BA HIST3H2BB HIST1H2BD MRE11Ap-T4827,SUMO1-HERC2 p-S140-H2AFX BARD1 NonhomologousEnd-Joining (NHEJ)HIST1H2BD BRCA1ATM alpha-particle HIST1H2BJ KDM4B HIST1H2BM Zn2+ HIST1H2BA RAD50 MRE11A HIST1H2BL H2BFS DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1:WHSC1p-T4827,SUMO1-HERC2 UBE2V2 HIST3H3 ADPHIST1H2BL p-T4827,SUMO1-HERC2 HIST1H2BO p-T68-CHEK2 p-S343-NBN BARD1 Zn2+ UBE2V2 p-S1981,Ac-K3016-ATM DNA double-strand break ends DNA double-strand break ends HIST3H2BB RNF168 p-5T-MDC1 UBE2N HERC2-SUMO1 HIST1H2BL HIST3H2BB K63PolyUb-K14,K16,p-S140-H2AFX K63PolyUb-K14,K16,p-S140-H2AFX RNF168 HIST1H2BM HIST1H2BD MRE11A H2BFS DNA double-strand break ends HIST1H2BH MRE11A HIST1H2BD p-Y143-H2AFX HIST3H3 HIST1H2BL NBNHIST1H2BJ UBE2V2 p-S343-NBN HIST1H2BH HIST1H2BB HIST1H2BA HIST1H2BC HIST1H2BM p-S1981,Ac-K3016-ATM ATPp-S140-H2AFX UBC(533-608) Zn2+ HIST2H2BE DNA double-strand break ends HIST1H2BN RNF8 p-T4827-HERC2 KAT5 p-S343-NBN HIST1H2BB HIST1H2BC HIST1H2BN RNF8 RAD50 ADPH2BFS HIST1H2BJ NBNPIAS4 H2BFS HIST1H2BL RNF8 MRE11A KAT5 HIST1H2BH UBE2N DNADSBs:MRN:Ac-K3016-ATM dimer:KAT5H2BFS HIST3H3 HIST1H2BM HIST1H2BJ HIST1H2BK HIST1H2BK BRCC3 H2OH2BFS p-5T-MDC1 HIST1H2BH HIST1H4 DNA double-strand break ends HIST1H2BB KAT5 HIST1H2BC p-S140,Y143-H2AFX HIST3H3 UBE2V2 DNA double-strand break ends HIST1H2BL BABAM1 HIST1H2BL HIST1H2BD p-S140-H2AFX HIST1H2BB PIAS4 UBE2V2 HIST1H2BM HIST2H2BE DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1:p-S102-WHSC1p-T4827,SUMO1-HERC2 HIST1H2BO DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4KDM4B DNA double-strand break ends HIST1H2BC Me2K21-HIST1H4 ATPKPNA2PiHIST1H2BN DNA double-strand break ends HIST3H3 HIST1H2BA p-S102-WHSC1 ATPHIST2H2BE KAT5 TP53BP1 p-S140-H2AFX HIST1H2BJ HIST1H4 H2BFS H2BFS HIST1H2BL Me2K21-HIST1H4 p-S1981,Ac-K3016-ATM HIST1H2BK HIST1H2BL K63PolyUb-K14,K16,p-S140-H2AFX KAT5 HIST1H2BL DNA double-strand break ends HIST1H2BB RAD50 HIST1H2BH HIST1H2BN HIST1H2BA HIST2H2BE RNF8 HIST3H2BB HIST1H2BL HIST1H2BN HIST1H2BJ HIST3H3 HIST3H3 KDM4A MRE11A HIST1H2BO HIST1H2BM HIST1H2BH p-S343-NBN Me2K21-HIST1H4 DNA double-strand break ends MRE11A MRE11A HIST1H2BC MRE11A DNADNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex:CHEK2HIST1H2BA ADPp-5T-MDC1 RNF168 UBB(1-76) HIST3H2BB DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:PIAS4HIST2H2BE HIST1H2BH p-S140-H2AFX HIST1H2BK WICHHIST1H2BH ATPRNF168 HIST1H2BD HIST1H2BL HIST1H2BC HDR through MMEJ(alt-NHEJ)PIAS4 HIST1H2BK p-S1981,Ac-K3016-ATM p-S1981,Ac-K3016-ATM RNF8 HIST1H2BN p-5T-MDC1 Zn2+ p-T4827,SUMO1-HERC2 p-S1981,Ac-K3016-ATM p-S102-WHSC1 beta-particle K63PolyUb-K14,K16,p-S140-H2AFX HIST1H2BL RAD50 MRE11A p-5T-MDC1 HIST1H2BD p-5T-MDC1 HIST1H4 MRE11A HIST2H2BE HIST1H2BO p-S25,S1778-TP53BP1 p-S1981,Ac-K3016-ATM HIST1H2BA UBB(77-152) HIST1H2BJ UIMC1p-T4827,SUMO1-HERC2 HIST1H2BN p-S343-NBN BABAM1 KAT5 HDR throughHomologousRecombination (HRR)or Single StrandAnnealing (SSA)KDM4A HIST1H2BC HIST2H2BE HIST1H2BM p-S343-NBN BRE ROS RAD50 ATPADPHIST3H2BB HIST1H2BA HIST1H2BA Zn2+ KAT5 DNA double-strand break ends HIST1H2BC K63PolyUb-K14,K16,p-S140-H2AFX p-S1387,S1423,S1524,S1547-BRCA1 MRE11A DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1p-S1981,Ac-K3016-ATM BAP1:BARD1p-S343-NBN HIST1H2BD HIST1H2BK HIST1H2BN HIST1H2BJ HIST1H2BM HIST2H2BE RNF168 H2BFS H2BFS ADPHIST1H2BO p-S343-NBN HIST1H2BM HIST1H2BL HIST1H2BN PIAS4 RNF8 p-S1981,Ac-K3016-ATM DNA double-strand break ends HIST1H2BN PIAS4 ADPHIST1H2BC p-S343-NBN BRE HIST1H2BA DNA DSBs:MRN:ATMdimer:KAT5HIST1H2BK KDM4B KDM4B DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139,Y142-H2AFX-NucleosomeH2BFS p-S1981,Ac-K3016-ATM p-T4827,SUMO1-HERC2 HIST1H2BA HIST1H2BK RAD50 Me2K21-HIST1H4 HIST1H2BO KAT5 p-S1981,Ac-K3016-ATM p-S406-FAM175A H2BFS MRE11A p-S1981,Ac-K3016-ATM KDM4B DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139,Y142-H2AFX-Nucleosome:APBB1:p-T,Y-MAPK8NBN HIST3H3 HIST1H2BC HIST1H2BL HIST1H2BC HIST1H2BC KAT5 UBC(153-228) DNA double-strand break ends p-5T-MDC1 HIST1H2BO Me2K21-HIST1H4 p-5T-MDC1 HIST1H2BN HIST1H2BN TP53 TetramerAPBB1 HIST1H2BJ p-S1981,Ac-K3016-ATM NBN DNA double-strand break ends MRE11A p-S102-WHSC1 UBE2I-G97-SUMO1 MRE11A HIST1H2BH Me2K21-HIST1H4 X-ray UBB(153-228) p-EYA2 HIST3H3 HIST1H2BJ p-S102-WHSC1 KDM4A HIST1H2BH EYA3 HIST1H2BC DNADSBs:p-MRN:p-S-1981,Ac-K3016-ATM:KAT5:p-Y142-H2AFX-NucleosomeDNADNADSBs: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 complexp-S1981,Ac-K3016-ATM KDM4B ATM p-S343-NBN DNADNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:BRCA1-A complexKDM4A HIST1H2BC HIST1H2BJ Zn2+ AdoMetHERC2-SUMO1 HIST1H2BD DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4proton p-S1981,Ac-K3016-ATM HIST1H2BK p-S140-H2AFX HIST1H2BD RNF8 p-S1981,Ac-K3016-ATM EYA4 MRE11A BRCC3 HIST1H2BH p-S102-WHSC1 HIST1H2BA HIST1H2BM HIST2H2BE HIST1H2BC Zn2+ DNA double-strand break ends HIST1H2BJ Me2K21-HIST1H4 BRE ATPHIST1H2BO HIST1H2BA p-T714,T734-BARD1 UBE2V2 KAT5 H2AFX HIST1H2BC DNADNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1ATPHIST1H2BH DNADSBs:MRN:p-S1981,Ac-K3016-ATM:KAT5BABAM1 Me2K21-HIST1H4 MRE11A UBC(1-76) HIST1H2BC Ac-K3016-ATM p-S140-H2AFX HIST3H2BB HIST1H4 HIST1H2BB HIST1H2BB p-S102-WHSC1 p-5T-MDC1 HIST1H2BK HIST3H2BB p-S406-FAM175A HIST1H2BC NBN:KPNA2DNA double-strand break ends Me2K21-HIST1H4 HIST1H2BH p-S1981,Ac-K3016-ATM HIST1H2BJ HIST1H2BA RNF168 p-S343-NBN HIST1H2BO HIST1H2BB RAD50 KAT5 HIST1H2BJ p-S1981,Ac-K3016-ATM DNA double-strand break ends HIST3H3 p-S1981,Ac-K3016-ATM H2BFS p-S15-TP53 UIMC1 WHSC1 H2BFS UBE2IMRE11A HIST3H2BB H2BFS p-5T-MDC1 ABL1KAT5 RNF168 HIST1H2BH HIST2H2BE HIST3H3 HIST1H2BD UbMe2K21-HIST1H4 RAD50 HIST1H2BK p-S102-WHSC1 HIST1H2BB EYA1 HERC2p-S406-FAM175AATM dimer:KAT5HERC2-SUMO1 H2BFS p-S140-H2AFX p-S343-NBN UBC(381-456) HIST2H2BE HIST2H2BE KAT5 HIST1H2BH Zn2+ DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:HERC2:PIAS4p-S1981,Ac-K3016-ATM HIST2H2BE ADPHERC2-SUMO1 UBE2N HIST1H2BL H2BFS HIST1H2BH HIST1H2BM NBN HIST1H2BO APBB1HIST1H2BN p-T68-CHEK2 dimerNBN HIST1H2BJ HIST2H2BE HIST1H2BJ DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1H2AFX-NucleosomeHIST3H2BB RNF8 MRE11A p-S343-NBN RAD50RAD50 RNF8 DNA double-strand break ends HIST3H2BB NBN HIST3H3 RNF168 HIST1H2BK HIST1H2BL HERC2-SUMO1 HIST1H2BD HIST3H3 HIST1H2BO p-S102-WHSC1 DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:PIAS4BREHIST1H2BJ DNA double-strand break ends HIST1H2BH ATPMRE11A p-S140-H2AFX HIST1H2BA p-S343-NBN HIST1H2BJ HIST1H2BB PIAS4 HIST1H4 HIST3H3 p-S,3T-CHEK2MRE11A HIST1H4 RNF8 DNA double-strand break ends p-S140-H2AFX HIST1H2BO KAT5 BAZ1B HIST2H2BE DNADSB:p-MRN:p-S1981,Ac-K3016-ATM:KAT5MRNHIST1H2BM p-Y143-H2AFX UBE2N HIST2H2BE HIST1H2BN p-S1981,Ac-K3016-ATM p-Y142-H2AFX-NucleosomeHIST2H2BE p-S1981,Ac-K3016-ATM HIST1H2BM H2BFS p-S406-FAM175A HIST1H2BD p-S25,S1778-TP53BP1 KDM4A RNF8 K48PolyUb-KDM4A,BBARD1 RAD50 HIST1H2BB HIST1H2BC KDM4B HIST1H2BL DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1HIST1H2BA p-5T-MDC1 MDC1 HIST3H2BB Zn2+ HIST3H3 HIST1H2BB p-S343-NBN HIST1H2BD HIST1H2BB p-5T-MDC1 KAT5 MRE11A RNF168 p-S102-WHSC1 HIST1H2BO RAD50 UBA52(1-76) HIST1H2BN PIAS4 SMARCA5 KAT5 HIST1H2BC HIST1H2BL BARD1HIST1H2BD HIST3H3 p-5T-MDC1 HIST1H2BM HIST1H2BK HIST1H2BB ADPp-T68-CHEK2H2BFS HIST1H2BK MRE11A PIAS4 p-S343-NBN UBC(77-152) HIST1H2BK HIST1H2BL p-S15-TP53 TetramerHIST1H2BA p-S343-NBN HIST3H3 RAD50 RAD50 Pip-S140,Y143-H2AFX p-S1981,Ac-K3016-ATMHIST1H2BA HERC2-SUMO1 BRE HIST2H2BE ATPRNF8:Zn2+MRE11A HIST3H3 HIST1H2BM MRE11A RAD50:MRE11AHIST2H2BE HIST1H2BO HIST3H2BB RNF8 HIST1H2BH HIST1H2BO KAT5 p-S1981,Ac-K3016-ATM HIST1H2BJ HIST1H2BA H2BFS p-5T-MDC1 HIST1H2BB p-EYA1 KAT5 p-S343-NBN HIST3H2BB HIST1H2BB BRCA1:BARD1HIST1H2BJ RNF168p-S1981,Ac-K3016-ATM RAD50 p-T4827,SUMO1-HERC2 HIST1H2BA HIST1H2BK UBE2V2 HIST1H2BO HIST3H3 HIST1H2BL HIST1H2BJ HIST2H2BE HIST1H2BO HIST1H2BB HIST1H2BL HIST1H2BH ATPp-EYA3 KDM4B DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+MRE11A p-S343-NBN K63PolyUb-K14,K16,p-S140-H2AFX UBE2N:UBE2V2ATPDNA double-strand break ends RNF8 p-S102-WHSC1 HIST1H2BD PIAS4 HIST1H2BM MRE11A HIST3H2BB Me2K21-HIST1H4 RAD50 UBE2N KDM4A HIST1H2BC HIST3H2BB BRCC3 ADPPIAS4 p-S1981,Ac-K3016-ATM p-T714,T734-BARD1 CHEK2 HIST1H2BJ HIST1H2BD HIST1H2BB TP53 RAD50 UIMC1 HIST3H3 HIST1H2BB p-S343-NBN UIMC1 RAD50 HIST1H2BC HIST1H2BO SUMO1-C93-UBE2I HIST1H2BN UBC(609-684) HIST1H2BN PPP5CDNA DSBs:MRNHIST3H3 Zn2+ RAD50 HIST1H2BM H2OHIST2H2BE DNA double-strandbreak endsHIST1H2BH HIST3H2BB HIST3H2BB MRE11A MRE11A HIST1H2BK HIST1H4 p-S406-FAM175A RNF168 RAD50 HIST1H2BD p-EYA1-4HIST1H2BA RAD50 ADPHIST3H3 HIST1H2BK p-S102-WHSC1 HIST1H2BH HERC2-SUMO1 HIST1H2BJ UBC(305-380) RPS27A(1-76) HIST1H2BA K63PolyUb-K14,K16,p-S140-H2AFX UBE2N UBE2N DNA double-strand break ends DNADNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complexHIST1H2BC KDM4A HIST1H2BN HIST1H2BK p-5T-MDC1 HIST1H2BD KAT5 UBC(229-304) H2BFS HIST1H2BO p-S25,S1778-TP53BP1 p-S406-FAM175A HIST1H2BJ Ac-CoAKDM4B HIST1H2BO HIST1H2BH p-S140-H2AFX RAD50 HIST1H2BL HIST1H2BD HIST1H2BA BAP1 UBE2N KAT5 UBE2N RAD50 CHEK2HIST1H2BM HIST1H2BN EYA2 Me2K21-HIST1H4 HIST1H2BD HIST1H2BK HIST1H4 p-S140-H2AFX RAD50 PIAS4 p-S102-WHSC1 HIST1H2BM ADPHIST1H2BO HIST3H3 HIST1H2BB p-S102-WHSC1 DNA double-strand break ends HIST3H3 K48PolyUb-KDM4A p-5T-MDC1 HIST1H2BH DNADSBs: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:PIAS4RAD50 HIST2H2BE p-T4827,SUMO1-HERC2 HIST1H2BO MRE11A p-S343-NBN HERC2-SUMO1 HIST1H2BK ATPHIST1H2BB KPNA2p-T4827,SUMO1-HERC2 p-S343-NBN HIST3H2BB HIST1H2BK DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:p-T4827-HERC2:PIAS4RAD50 HIST1H2BL p-S456-ABL1p-S988,S1387,S1423,S1524,S1547-BRCA1 HIST1H2BM HIST1H2BM p-S25,S1778-TP53BP1 HIST3H2BB PIAS4 p-S343-NBN RAD50 HERC2-SUMO1 HIST1H2BC p-S25,S1778-TP53BP1 HIST1H2BK HIST1H2BO BRCA1 HIST1H2BO dsDNAH2BFS RAD50 CoA-SHHIST2H2BE KAT5 HIST1H2BH HIST1H2BC HIST1H2BN BABAM1 Zn2+ HIST1H2BC HIST2H2BE HIST2H2BE DNA double-strand break ends RNF8 p-T,Y-MAPK8HIST1H2BN UBE2N Zn2+ p-T,Y-MAPK8 KAT5 UBE2N RAD50 HIST1H2BM KPNA2 ATPHIST1H2BC HIST1H2BJ p-S343-NBN PIAS4 UBE2V2 HIST1H2BM HIST1H2BD ATPHIST3H2BB DNA double-strand break ends BRCC3 p-S140-H2AFX HIST1H2BN p-EYA4 ATPHIST2H2BE HERC2-SUMO1 Zn2+ BRCA1 KAT5 HIST3H2BB HERC2 DNA double-strand break ends RAD50 HIST1H2BD K63PolyUb-K14,K16,p-S140-H2AFX p-S102-WHSC1 UBE2N HIST1H2BJ PIAS4PIAS4 Me2K21-HIST1H4 UBC(457-532) HERC2-SUMO1 SUMO1:C93-UBE2IADPHIST1H2BL HIST1H2BN Me2K21-HIST1H4 HIST1H2BB HIST1H4 KDM4A,BUBE2V2 HIST1H2BK KAT5 p-S1981,Ac-K3016-ATM H2BFS HIST1H2BK HIST1H4 K48PolyUb-KDM4B ADPKAT5 DNADNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:TP53BP1ADPMDC1 RAD50 p-T714,T734-BARD1 HIST1H2BO HIST1H2BB p-S102-WHSC1 p-S102-WHSC1 p-5T-MDC1 H2BFS H2BFS DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:MDC1KAT5 Me2K21-HIST1H4 HIST1H2BM HIST1H2BL HIST3H2BB p-5T-MDC1 HIST1H2BN HIST1H2BN DSB inducing agentsHIST1H2BA UBE2V2 RNF8 UIMC1 UBE2V2 HIST1H2BB HERC2-SUMO1 HIST1H2BO KDM4A Me2K21-HIST1H4 HIST1H2BB KDM4A MRE11A HIST1H2BB HIST1H2BA HIST3H2BB HIST1H2BD BRCC3p-5T-MDC1 HIST1H2BH AdoHcyHIST1H2BO TP53BP1HIST1H2BK p-S343-NBN Me2K21-HIST1H4 98, 10018189871341061821, 24, 30, 51, 52, 55...4181898100187, 9, 11, 12, 22...9918618346534101, 1193411698, 10079, 1067718189827181818181167518


Description

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. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 5693606
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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Bibliography

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  99. Lisby M, Barlow JH, Burgess RC, Rothstein R.; ''Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins.''; PubMed Europe PMC Scholia
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  101. Ciccia A, Elledge SJ.; ''The DNA damage response: making it safe to play with knives.''; PubMed Europe PMC Scholia
  102. 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
  103. Celeste A, Fernandez-Capetillo O, Kruhlak MJ, Pilch DR, Staudt DW, Lee A, Bonner RF, Bonner WM, Nussenzweig A.; ''Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks.''; PubMed Europe PMC Scholia
  104. Goldberg M, Stucki M, Falck J, D'Amours D, Rahman D, Pappin D, Bartek J, Jackson SP.; ''MDC1 is required for the intra-S-phase DNA damage checkpoint.''; PubMed Europe PMC Scholia
  105. Niewolik D, Pannicke U, Lu H, Ma Y, Wang LC, Kulesza P, Zandi E, Lieber MR, Schwarz K.; ''DNA-PKcs dependence of Artemis endonucleolytic activity, differences between hairpins and 5' or 3' overhangs.''; PubMed Europe PMC Scholia
  106. Ma Y, Pannicke U, Schwarz K, Lieber MR.; ''Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination.''; PubMed Europe PMC Scholia
  107. Fernandez-Capetillo O, Lee A, Nussenzweig M, Nussenzweig A.; ''H2AX: the histone guardian of the genome.''; PubMed Europe PMC Scholia
  108. Chen A, Kleiman FE, Manley JL, Ouchi T, Pan ZQ.; ''Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase.''; PubMed Europe PMC Scholia
  109. 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
  110. Sun Y, Xu Y, Roy K, Price BD.; ''DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity.''; PubMed Europe PMC Scholia
  111. Stewart GS, Panier S, Townsend K, Al-Hakim AK, Kolas NK, Miller ES, Nakada S, Ylanko J, Olivarius S, Mendez M, Oldreive C, Wildenhain J, Tagliaferro A, Pelletier L, Taubenheim N, Durandy A, Byrd PJ, Stankovic T, Taylor AM, Durocher D.; ''The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage.''; PubMed Europe PMC Scholia
  112. Cook PJ, Ju BG, Telese F, Wang X, Glass CK, Rosenfeld MG.; ''Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions.''; PubMed Europe PMC Scholia
  113. Mailand N, Bekker-Jensen S, Faustrup H, Melander F, Bartek J, Lukas C, Lukas J.; ''RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins.''; PubMed Europe PMC Scholia
  114. Fernandez-Capetillo O, Chen HT, Celeste A, Ward I, Romanienko PJ, Morales JC, Naka K, Xia Z, Camerini-Otero RD, Motoyama N, Carpenter PB, Bonner WM, Chen J, Nussenzweig A.; ''DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1.''; PubMed Europe PMC Scholia
  115. Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, Sedelnikova OA, Reina-San-Martin B, Coppola V, Meffre E, Difilippantonio MJ, Redon C, Pilch DR, Olaru A, Eckhaus M, Camerini-Otero RD, Tessarollo L, Livak F, Manova K, Bonner WM, Nussenzweig MC, Nussenzweig A.; ''Genomic instability in mice lacking histone H2AX.''; PubMed Europe PMC Scholia
  116. Kolas NK, Chapman JR, Nakada S, Ylanko J, Chahwan R, Sweeney FD, Panier S, Mendez M, Wildenhain J, Thomson TM, Pelletier L, Jackson SP, Durocher D.; ''Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase.''; PubMed Europe PMC Scholia
  117. Wilson KA, Stern DF.; ''NFBD1/MDC1, 53BP1 and BRCA1 have both redundant and unique roles in the ATM pathway.''; PubMed Europe PMC Scholia
  118. Laufer M, Nandula SV, Modi AP, Wang S, Jasin M, Murty VV, Ludwig T, Baer R.; ''Structural requirements for the BARD1 tumor suppressor in chromosomal stability and homology-directed DNA repair.''; PubMed Europe PMC Scholia
  119. Du F, Zhang M, Li X, Yang C, Meng H, Wang D, Chang S, Xu Y, Price B, Sun Y.; ''Dimer monomer transition and dimer re-formation play important role for ATM cellular function during DNA repair.''; PubMed Europe PMC Scholia
  120. 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
  121. Curtin NJ.; ''DNA repair dysregulation from cancer driver to therapeutic target.''; PubMed Europe PMC Scholia
  122. Wu-Baer F, Ludwig T, Baer R.; ''The UBXN1 protein associates with autoubiquitinated forms of the BRCA1 tumor suppressor and inhibits its enzymatic function.''; PubMed Europe PMC Scholia
  123. Kozlov SV, Graham ME, Peng C, Chen P, Robinson PJ, Lavin MF.; ''Involvement of novel autophosphorylation sites in ATM activation.''; PubMed Europe PMC Scholia
  124. Fan W, Wu X.; ''DNA polymerase lambda can elongate on DNA substrates mimicking non-homologous end joining and interact with XRCC4-ligase IV complex.''; PubMed Europe PMC Scholia
  125. Mattiroli F, Vissers JH, van Dijk WJ, Ikpa P, Citterio E, Vermeulen W, Marteijn JA, Sixma TK.; ''RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling.''; PubMed Europe PMC Scholia
  126. Zimmermann M, Lottersberger F, Buonomo SB, Sfeir A, de Lange T.; ''53BP1 regulates DSB repair using Rif1 to control 5' end resection.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114907view16:42, 25 January 2021ReactomeTeamReactome version 75
113352view11:42, 2 November 2020ReactomeTeamReactome version 74
112561view15:53, 9 October 2020ReactomeTeamReactome version 73
101474view11:33, 1 November 2018ReactomeTeamreactome version 66
101012view21:13, 31 October 2018ReactomeTeamreactome version 65
100548view19:47, 31 October 2018ReactomeTeamreactome version 64
100096view16:32, 31 October 2018ReactomeTeamreactome version 63
99646view15:03, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99248view12:44, 31 October 2018ReactomeTeamreactome version 62
93882view13:42, 16 August 2017ReactomeTeamreactome version 61
93450view11:23, 9 August 2017ReactomeTeamreactome version 61
87147view18:54, 18 July 2016MkutmonOntology Term : 'DNA damage response pathway' added !
86542view09:20, 11 July 2016ReactomeTeamreactome version 56
83433view12:24, 18 November 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ABL1ProteinP00519 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
APBB1 ProteinO00213 (Uniprot-TrEMBL)
APBB1ProteinO00213 (Uniprot-TrEMBL)
ATM ProteinQ13315 (Uniprot-TrEMBL)
ATM dimer:KAT5ComplexR-HSA-5682037 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
Ac-K3016-ATM ProteinQ13315 (Uniprot-TrEMBL)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
BABAM1 ProteinQ9NWV8 (Uniprot-TrEMBL)
BABAM1ProteinQ9NWV8 (Uniprot-TrEMBL)
BAP1 ProteinQ92560 (Uniprot-TrEMBL)
BAP1:BARD1ComplexR-HSA-5690771 (Reactome)
BARD1 ProteinQ99728 (Uniprot-TrEMBL)
BARD1ProteinQ99728 (Uniprot-TrEMBL)
BAZ1B ProteinQ9UIG0 (Uniprot-TrEMBL)
BRCA1 ProteinP38398 (Uniprot-TrEMBL)
BRCA1:BARD1ComplexR-HSA-5659802 (Reactome)
BRCA1ProteinP38398 (Uniprot-TrEMBL)
BRCC3 ProteinP46736 (Uniprot-TrEMBL)
BRCC3ProteinP46736 (Uniprot-TrEMBL)
BRE ProteinQ9NXR7 (Uniprot-TrEMBL)
BREProteinQ9NXR7 (Uniprot-TrEMBL)
CHEK2 ProteinO96017 (Uniprot-TrEMBL)
CHEK2ProteinO96017 (Uniprot-TrEMBL)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
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:TP53BP1		ComplexR-HSA-5693591 (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:BRCA1-A complex		ComplexR-HSA-5683387 (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:UIMC1:p-S406-FAM175A		ComplexR-HSA-5683388 (Reactome)
DNA

DNA

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

DNA

DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex		ComplexR-HSA-5683605 (Reactome)
DNA

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		ComplexR-HSA-5683808 (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		ComplexR-HSA-5683417 (Reactome)
DNA DSB:p-MRN:p-S1981,Ac-K3016-ATM:KAT5ComplexR-HSA-5682162 (Reactome)
DNA DSBs:MRN:Ac-K3016-ATM dimer:KAT5ComplexR-HSA-5682035 (Reactome)
DNA DSBs:MRN:p-S1981,Ac-K3016-ATM:KAT5ComplexR-HSA-5682055 (Reactome)
DNA DSBs:p-MRN:p-S-1981,Ac-K3016-ATM:KAT5:p-Y142-H2AFX-NucleosomeComplexR-HSA-5693563 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4ComplexR-HSA-5682861 (Reactome)
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:PIAS4ComplexR-HSA-5683079 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139,Y142-H2AFX-Nucleosome:APBB1:p-T,Y-MAPK8ComplexR-HSA-5683988 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139,Y142-H2AFX-NucleosomeComplexR-HSA-5683952 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:HERC2:PIAS4ComplexR-HSA-5682590 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:PIAS4ComplexR-HSA-5682609 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:PIAS4ComplexR-HSA-5682623 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4ComplexR-HSA-5682859 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:p-T4827-HERC2:PIAS4ComplexR-HSA-5682599 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+ComplexR-HSA-5682585 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1ComplexR-HSA-5682993 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1ComplexR-HSA-5682972 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:MDC1ComplexR-HSA-5693594 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1:WHSC1ComplexR-HSA-5682968 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1:p-S102-WHSC1ComplexR-HSA-5682976 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1ComplexR-HSA-5682530 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-NucleosomeComplexR-HSA-5682180 (Reactome)
DNA DSBs:MRN:ATM dimer:KAT5ComplexR-HSA-3785779 (Reactome)
DNA DSBs:MRNComplexR-HSA-3785763 (Reactome)
DNA double-strand break endsR-ALL-75165 (Reactome)
DNA double-strand break ends R-ALL-75165 (Reactome)
DSB inducing agentsComplexR-ALL-6783909 (Reactome)
EYA1 ProteinQ99502 (Uniprot-TrEMBL)
EYA1-4ComplexR-HSA-5683966 (Reactome)
EYA2 ProteinO00167 (Uniprot-TrEMBL)
EYA3 ProteinQ99504 (Uniprot-TrEMBL)
EYA4 ProteinO95677 (Uniprot-TrEMBL)
H2AFX ProteinP16104 (Uniprot-TrEMBL)
H2AFX-NucleosomeComplexR-HSA-975775 (Reactome)
H2BFS ProteinP57053 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
HDR through

Homologous Recombination (HRR) or Single Strand

Annealing (SSA)		PathwayR-HSA-5693567 (Reactome) Homology directed repair (HDR) of replication-independent DNA double strand breaks (DSBs) via homologous recombination repair (HRR) or single strand annealing (SSA) requires the activation of ATM followed by ATM-mediated phosphorylation of DNA repair proteins. ATM coordinates the recruitment of DNA repair and signaling proteins to DSBs and formation of the so-called ionizing radiation induced foci (IRIF). While IRIFs include chromatin regions kilobases away from the actual DSB, this Reactome pathway represents simplified foci and shows events that happen at the very ends of the broken DNA.

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.

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.

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).

HDR through MMEJ (alt-NHEJ)PathwayR-HSA-5685939 (Reactome) Homology directed repair (HDR) through microhomology-mediated end joining (MMEJ) is an error prone process also known as alternative nonhomologous end joining (alt-NHEJ), although it does not involve proteins that participate in the classical NHEJ. Contrary to the classical NHEJ and other HDR pathways, homologous recombination repair (HRR) and single strand annealing (SSA), MMEJ does not require ATM activation. In fact, ATM activation inhibits MMEJ. Therefore, MMEJ may be triggered when the amount of DNA double strand breaks (DSBs) overwhelms DNA repair machinery of higher fidelity or when cells are deficient in components of high fidelity DNA repair.

MMEJ is initiated by a limited resection of DNA DSB ends by the MRN complex (MRE11A:RAD50:NBN) and RBBP8 (CtIP), in the absence of CDK2-mediated RBBP8 phosphorylation and related BRCA1:BARD1 recruitment (Yun and Hiom 2009). Single strand DNA (ssDNA) at resected DNA DSB ends recruits PARP1 or PARP2 homo- or heterodimers, together with DNA polymerase theta (POLQ) and FEN1 5'-flap endonuclease. In a poorly studied sequence of events, POLQ promotes the annealing of two 3'-ssDNA overhangs through microhomologous regions that are optimally 10-19 nucleotides long. Using analogy with POLB-mediated long patch base excision repair (BER), it is plausible that PARP1 (or PARP2) dimers coordinate the extension of annealed 3'-ssDNA overhangs via POLQ-mediated strand displacement synthesis with FEN1-mediated cleavage of the resulting 5'-flaps (Liang et al. 2005, Mansour et al. 2011, Sharma et al. 2015, Kent et al. 2015, Ciccaldi et al. 2015, Mateos-Gomez et al. 2015). The MRN complex subsequently recruits DNA ligase 3 (LIG3) bound to XRCC1 (LIG3:XRCC1) to ligate the remaining single strand nicks (SSBs) at MMEJ sites (Della-Maria et al. 2011).

Similar to single strand annealing (SSA), MMEJ leads to deletion of one of the microhomology regions used for annealing and the DNA sequence in between two annealed microhomology regions. MMEJ, just like classical NHEJ, can result in genomic translocations (Ghezraoui et al. 2014). In addition, since POLQ is an error-prone DNA polymerase, MMEJ introduces frequent base substitutions (Ceccaldi et al. 2015).

HERC2 ProteinO95714 (Uniprot-TrEMBL)
HERC2-SUMO1 ProteinP63165 (Uniprot-TrEMBL)
HERC2ProteinO95714 (Uniprot-TrEMBL)
HIST1H2BA ProteinQ96A08 (Uniprot-TrEMBL)
HIST1H2BB ProteinP33778 (Uniprot-TrEMBL)
HIST1H2BC ProteinP62807 (Uniprot-TrEMBL)
HIST1H2BD ProteinP58876 (Uniprot-TrEMBL)
HIST1H2BH ProteinQ93079 (Uniprot-TrEMBL)
HIST1H2BJ ProteinP06899 (Uniprot-TrEMBL)
HIST1H2BK ProteinO60814 (Uniprot-TrEMBL)
HIST1H2BL ProteinQ99880 (Uniprot-TrEMBL)
HIST1H2BM ProteinQ99879 (Uniprot-TrEMBL)
HIST1H2BN ProteinQ99877 (Uniprot-TrEMBL)
HIST1H2BO ProteinP23527 (Uniprot-TrEMBL)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST2H2BE ProteinQ16778 (Uniprot-TrEMBL)
HIST3H2BB ProteinQ8N257 (Uniprot-TrEMBL)
HIST3H3 ProteinQ16695 (Uniprot-TrEMBL)
K48PolyUb-KDM4A ProteinO75164 (Uniprot-TrEMBL)
K48PolyUb-KDM4A,BComplexR-HSA-5683075 (Reactome)
K48PolyUb-KDM4B ProteinO94953 (Uniprot-TrEMBL)
K63PolyUb-K14,K16,p-S140-H2AFX ProteinP16104 (Uniprot-TrEMBL)
KAT5 ProteinQ92993 (Uniprot-TrEMBL)
KDM4A ProteinO75164 (Uniprot-TrEMBL)
KDM4A,BComplexR-HSA-5682990 (Reactome)
KDM4B ProteinO94953 (Uniprot-TrEMBL)
KPNA2 ProteinP52292 (Uniprot-TrEMBL)
KPNA2ProteinP52292 (Uniprot-TrEMBL)
MDC1 ProteinQ14676 (Uniprot-TrEMBL)
MDC1ComplexR-HSA-5682522 (Reactome)
MRE11A ProteinP49959 (Uniprot-TrEMBL)
MRE11AProteinP49959 (Uniprot-TrEMBL)
MRNComplexR-HSA-75164 (Reactome)
Me2K21-HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
NBN ProteinO60934 (Uniprot-TrEMBL)
NBN:KPNA2ComplexR-HSA-5684011 (Reactome)
NBNProteinO60934 (Uniprot-TrEMBL)
Nonhomologous End-Joining (NHEJ)PathwayR-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).
PIAS4 ProteinQ8N2W9 (Uniprot-TrEMBL)
PIAS4ProteinQ8N2W9 (Uniprot-TrEMBL)
PPP5CProteinP53041 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
RAD50 ProteinQ92878 (Uniprot-TrEMBL)
RAD50:MRE11AComplexR-HSA-75161 (Reactome)
RAD50ProteinQ92878 (Uniprot-TrEMBL)
RNF168 ProteinQ8IYW5 (Uniprot-TrEMBL)
RNF168ProteinQ8IYW5 (Uniprot-TrEMBL)
RNF8 ProteinO76064 (Uniprot-TrEMBL)
RNF8:Zn2+ComplexR-HSA-5682540 (Reactome)
ROS MetaboliteCHEBI:26523 (ChEBI)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SMARCA5 ProteinO60264 (Uniprot-TrEMBL)
SUMO1-C93-UBE2I ProteinP63279 (Uniprot-TrEMBL)
SUMO1:C93-UBE2IComplexR-HSA-2993783 (Reactome)
TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 TetramerComplexR-HSA-3209194 (Reactome)
TP53BP1 ProteinQ12888 (Uniprot-TrEMBL)
TP53BP1ProteinQ12888 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UBE2I-G97-SUMO1 ProteinP63165 (Uniprot-TrEMBL)
UBE2IProteinP63279 (Uniprot-TrEMBL)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2N:UBE2V2ComplexR-HSA-5682542 (Reactome)
UBE2V2 ProteinQ15819 (Uniprot-TrEMBL)
UIMC1 ProteinQ96RL1 (Uniprot-TrEMBL)
UIMC1ProteinQ96RL1 (Uniprot-TrEMBL)
UbComplexR-HSA-68524 (Reactome)
WHSC1 ProteinO96028 (Uniprot-TrEMBL)
WHSC1ProteinO96028 (Uniprot-TrEMBL)
WICHComplexR-HSA-5683941 (Reactome)
X-ray MetaboliteCHEBI:30212 (ChEBI)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
alpha-particle MetaboliteCHEBI:30216 (ChEBI)
beta-particle MetaboliteCHEBI:10545 (ChEBI)
dsDNAR-HSA-5649637 (Reactome)
gamma-ray MetaboliteCHEBI:30212 (ChEBI)
p-5T-MDC1 ProteinQ14676 (Uniprot-TrEMBL)
p-EYA1 ProteinQ99502 (Uniprot-TrEMBL)
p-EYA1-4ComplexR-HSA-5683980 (Reactome)
p-EYA2 ProteinO00167 (Uniprot-TrEMBL)
p-EYA3 ProteinQ99504 (Uniprot-TrEMBL)
p-EYA4 ProteinO95677 (Uniprot-TrEMBL)
p-S,3T-CHEK2ProteinO96017 (Uniprot-TrEMBL)
p-S102-WHSC1 ProteinO96028 (Uniprot-TrEMBL)
p-S1387,S1423,S1524,S1547-BRCA1 ProteinP38398 (Uniprot-TrEMBL)
p-S140,Y143-H2AFX ProteinP16104 (Uniprot-TrEMBL)
p-S140-H2AFX ProteinP16104 (Uniprot-TrEMBL)
p-S15-TP53 ProteinP04637 (Uniprot-TrEMBL)
p-S15-TP53 TetramerComplexR-HSA-349474 (Reactome)
p-S1981,Ac-K3016-ATM ProteinQ13315 (Uniprot-TrEMBL)
p-S1981,Ac-K3016-ATMProteinQ13315 (Uniprot-TrEMBL)
p-S25,S1778-TP53BP1 ProteinQ12888 (Uniprot-TrEMBL)
p-S343-NBN ProteinO60934 (Uniprot-TrEMBL)
p-S406-FAM175A ProteinQ6UWZ7 (Uniprot-TrEMBL)
p-S406-FAM175AProteinQ6UWZ7 (Uniprot-TrEMBL)
p-S456-ABL1ProteinP00519 (Uniprot-TrEMBL)
p-S988,S1387,S1423,S1524,S1547-BRCA1 ProteinP38398 (Uniprot-TrEMBL)
p-T,Y-MAPK8 ProteinP45983 (Uniprot-TrEMBL)
p-T,Y-MAPK8ProteinP45983 (Uniprot-TrEMBL)
p-T4827,SUMO1-HERC2 ProteinO95714 (Uniprot-TrEMBL)
p-T4827-HERC2 ProteinO95714 (Uniprot-TrEMBL)
p-T68-CHEK2 ProteinO96017 (Uniprot-TrEMBL)
p-T68-CHEK2 dimerComplexR-HSA-5683773 (Reactome)
p-T68-CHEK2ProteinO96017 (Uniprot-TrEMBL)
p-T714,T734-BARD1 ProteinQ99728 (Uniprot-TrEMBL)
p-Y142-H2AFX-NucleosomeComplexR-HSA-5683932 (Reactome)
p-Y143-H2AFX ProteinP16104 (Uniprot-TrEMBL)
proton MetaboliteCHEBI:24636 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ABL1R-HSA-5686578 (Reactome)
ADPArrowR-HSA-5682598 (Reactome)
ADPArrowR-HSA-5682983 (Reactome)
ADPArrowR-HSA-5683425 (Reactome)
ADPArrowR-HSA-5683792 (Reactome)
ADPArrowR-HSA-5683801 (Reactome)
ADPArrowR-HSA-5683930 (Reactome)
ADPArrowR-HSA-5683964 (Reactome)
ADPArrowR-HSA-5686578 (Reactome)
ADPArrowR-HSA-5693536 (Reactome)
ADPArrowR-HSA-5693540 (Reactome)
ADPArrowR-HSA-5693549 (Reactome)
ADPArrowR-HSA-5693551 (Reactome)
ADPArrowR-HSA-5693598 (Reactome)
ADPArrowR-HSA-5693609 (Reactome)
ADPArrowR-HSA-69891 (Reactome)
APBB1R-HSA-5683986 (Reactome)
ATM dimer:KAT5R-HSA-5693612 (Reactome)
ATPR-HSA-5682598 (Reactome)
ATPR-HSA-5682983 (Reactome)
ATPR-HSA-5683425 (Reactome)
ATPR-HSA-5683792 (Reactome)
ATPR-HSA-5683801 (Reactome)
ATPR-HSA-5683930 (Reactome)
ATPR-HSA-5683964 (Reactome)
ATPR-HSA-5686578 (Reactome)
ATPR-HSA-5693536 (Reactome)
ATPR-HSA-5693540 (Reactome)
ATPR-HSA-5693549 (Reactome)
ATPR-HSA-5693551 (Reactome)
ATPR-HSA-5693598 (Reactome)
ATPR-HSA-5693609 (Reactome)
ATPR-HSA-69891 (Reactome)
Ac-CoAR-HSA-5682044 (Reactome)
AdoHcyArrowR-HSA-5682965 (Reactome)
AdoMetR-HSA-5682965 (Reactome)
BABAM1R-HSA-5683385 (Reactome)
BAP1:BARD1TBarR-HSA-5659781 (Reactome)
BARD1R-HSA-5659781 (Reactome)
BRCA1:BARD1ArrowR-HSA-5659781 (Reactome)
BRCA1:BARD1R-HSA-5683385 (Reactome)
BRCA1R-HSA-5659781 (Reactome)
BRCC3R-HSA-5683385 (Reactome)
BRER-HSA-5683385 (Reactome)
CHEK2R-HSA-5683735 (Reactome)
CoA-SHArrowR-HSA-5682044 (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:TP53BP1		ArrowR-HSA-5683405 (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:TP53BP1		ArrowR-HSA-5693566 (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:TP53BP1		R-HSA-5683425 (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:TP53BP1		mim-catalysisR-HSA-5683425 (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:BRCA1-A complex		ArrowR-HSA-5683385 (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:BRCA1-A complex		R-HSA-5693551 (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:BRCA1-A complex		mim-catalysisR-HSA-5693551 (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:UIMC1:p-S406-FAM175A		ArrowR-HSA-5683384 (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:UIMC1:p-S406-FAM175A		R-HSA-5683385 (Reactome)
DNA

DNA

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

DNA

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

DNA

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

DNA

DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex		ArrowR-HSA-5693551 (Reactome)
DNA

DNA

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

DNA

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

DNA

DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex		R-HSA-5683801 (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		ArrowR-HSA-5683801 (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		ArrowR-HSA-5683425 (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		R-HSA-5683384 (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		R-HSA-5683405 (Reactome)
DNA DSB:p-MRN:p-S1981,Ac-K3016-ATM:KAT5ArrowR-HSA-5693598 (Reactome)
DNA DSB:p-MRN:p-S1981,Ac-K3016-ATM:KAT5R-HSA-5693602 (Reactome)
DNA DSBs:MRN:Ac-K3016-ATM dimer:KAT5ArrowR-HSA-5682044 (Reactome)
DNA DSBs:MRN:Ac-K3016-ATM dimer:KAT5R-HSA-5693540 (Reactome)
DNA DSBs:MRN:Ac-K3016-ATM dimer:KAT5mim-catalysisR-HSA-5693540 (Reactome)
DNA DSBs:MRN:p-S1981,Ac-K3016-ATM:KAT5ArrowR-HSA-5693540 (Reactome)
DNA DSBs:MRN:p-S1981,Ac-K3016-ATM:KAT5R-HSA-5693598 (Reactome)
DNA DSBs:MRN:p-S1981,Ac-K3016-ATM:KAT5mim-catalysisR-HSA-5693598 (Reactome)
DNA DSBs:p-MRN:p-S-1981,Ac-K3016-ATM:KAT5:p-Y142-H2AFX-NucleosomeArrowR-HSA-5693602 (Reactome)
DNA DSBs:p-MRN:p-S-1981,Ac-K3016-ATM:KAT5:p-Y142-H2AFX-NucleosomeR-HSA-5693549 (Reactome)
DNA DSBs:p-MRN:p-S-1981,Ac-K3016-ATM:KAT5:p-Y142-H2AFX-Nucleosomemim-catalysisR-HSA-5693549 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4ArrowR-HSA-5682858 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4R-HSA-5683077 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4mim-catalysisR-HSA-5683077 (Reactome)
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:PIAS4ArrowR-HSA-5683077 (Reactome)
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:PIAS4R-HSA-5693566 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139,Y142-H2AFX-Nucleosome:APBB1:p-T,Y-MAPK8ArrowR-HSA-5683986 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139,Y142-H2AFX-NucleosomeArrowR-HSA-5693549 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139,Y142-H2AFX-NucleosomeR-HSA-5683967 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139,Y142-H2AFX-NucleosomeR-HSA-5683986 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139,Y142-H2AFX-Nucleosomemim-catalysisR-HSA-5683964 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:HERC2:PIAS4ArrowR-HSA-5682586 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:HERC2:PIAS4R-HSA-5682598 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:HERC2:PIAS4mim-catalysisR-HSA-5682598 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:PIAS4ArrowR-HSA-5682607 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:PIAS4R-HSA-5682629 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:PIAS4ArrowR-HSA-5682629 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:PIAS4R-HSA-5682863 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4ArrowR-HSA-5682863 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4R-HSA-5682858 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4mim-catalysisR-HSA-5682858 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:p-T4827-HERC2:PIAS4ArrowR-HSA-5682598 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:p-T4827-HERC2:PIAS4R-HSA-5682607 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:p-T4827-HERC2:PIAS4mim-catalysisR-HSA-5682607 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+ArrowR-HSA-5682588 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+R-HSA-5682586 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1ArrowR-HSA-5682992 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1R-HSA-5682588 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1ArrowR-HSA-5682965 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1R-HSA-5682992 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:MDC1ArrowR-HSA-5693583 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:MDC1R-HSA-5693536 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:MDC1mim-catalysisR-HSA-5693536 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1:WHSC1ArrowR-HSA-5682967 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1:WHSC1R-HSA-5682983 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1:WHSC1mim-catalysisR-HSA-5682983 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1:p-S102-WHSC1ArrowR-HSA-5682983 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1:p-S102-WHSC1R-HSA-5682965 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1:p-S102-WHSC1mim-catalysisR-HSA-5682965 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1ArrowR-HSA-5693536 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1R-HSA-5682967 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-NucleosomeArrowR-HSA-5683967 (Reactome)
DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-NucleosomeR-HSA-5693583 (Reactome)
DNA DSBs:MRN:ATM dimer:KAT5ArrowR-HSA-5693612 (Reactome)
DNA DSBs:MRN:ATM dimer:KAT5R-HSA-5682044 (Reactome)
DNA DSBs:MRN:ATM dimer:KAT5mim-catalysisR-HSA-5682044 (Reactome)
DNA DSBs:MRNArrowR-HSA-3785768 (Reactome)
DNA DSBs:MRNR-HSA-5693612 (Reactome)
DNA double-strand break endsArrowR-HSA-3785704 (Reactome)
DNA double-strand break endsR-HSA-3785768 (Reactome)
DSB inducing agentsR-HSA-3785704 (Reactome)
EYA1-4R-HSA-5683964 (Reactome)
H2AFX-NucleosomeR-HSA-5683930 (Reactome)
H2OR-HSA-5683405 (Reactome)
H2OR-HSA-5683967 (Reactome)
HERC2R-HSA-5682586 (Reactome)
K48PolyUb-KDM4A,BArrowR-HSA-5683077 (Reactome)
KDM4A,BR-HSA-5682992 (Reactome)
KPNA2ArrowR-HSA-5684006 (Reactome)
KPNA2R-HSA-5684008 (Reactome)
MDC1R-HSA-5693583 (Reactome)
MRE11AR-HSA-75172 (Reactome)
MRNArrowR-HSA-75174 (Reactome)
MRNR-HSA-3785768 (Reactome)
NBN:KPNA2ArrowR-HSA-5684008 (Reactome)
NBN:KPNA2R-HSA-5684006 (Reactome)
NBNArrowR-HSA-5684006 (Reactome)
NBNR-HSA-5684008 (Reactome)
NBNR-HSA-75174 (Reactome)
PIAS4R-HSA-5682586 (Reactome)
PPP5Cmim-catalysisR-HSA-5683405 (Reactome)
PiArrowR-HSA-5683405 (Reactome)
PiArrowR-HSA-5683967 (Reactome)
R-HSA-3785704 (Reactome) Reactive oxygen species (ROS) induce DNA double strand breaks (DSBs) (Yu and Anderson 1997) in cells undergoing oxidative stress. In addition to ROS, DSBs can also be directly generated by ionizing radiation. Agents that interfere with the progression of replication forks, such as topoisomerase poisons used in chemotherapy, induce DSBs indirectly (Curtin 2012).
R-HSA-3785768 (Reactome) The MRN complex (MRE11A:RAD50:NBN) binds to DNA ends found at double strand breaks (DNA DSBs) (Lee and Paull 2005). In budding yeast, the Mre11:Rad50:Xrs2 complex, homologous to human MRN, rapidly localizes to DNA breaks (Shroff et al. 2004, Lisby et al. 2004).
R-HSA-5659781 (Reactome) BRCA1 and BARD1 form a stable heterodimer through interaction of their RING domain-containing N-termini (Wu et al. 1996, Brzovic et al. 2001). Both BRCA1 and BARD1 have a RING domain in their N-terminal regions and tandem BRCT motifs at their C termini. The central region of BARD1 contains ankyrin repeats (Wu et al. 1996). Formation of BRCA1:BARD1 heterodimers is necessary for the repair of double strand DNA breaks by homologous recombination (Westermark et al. 2003, Laufer et al. 2007) and for the function of BRCA1 in tumor suppression (Shakya et al. 2008) and normal development (McCarthy et al. 2003). Tumorigenic BRCA1 and BARD1 mutations that abolish formation of BRCA1:BARD1 heterodimers have been reported (Wu et al. 1996, Brzovic et al. 2001, Morris et al. 2002, Caleca et al. 2014).
R-HSA-5682044 (Reactome) The histone acetyltransferase Tip60 (KAT5), in addition to forming a histone acetyltransferase complex with NuA4, forms another complex with ATM dimers. The ATM dimer:KAT5 complex is formed in the absence of DNA damage, but the acetyltransferase activity of KAT5 is activated by double strand DNA breaks (DNA DSBs) (Sun et al. 2005). In response to DNA DSBs, the MRN complex targets KAT5 to chromatin, where KAT5 associates with histone H3 trimethylated on lysine 10 (commonly known as H3K9me3 mark). Besides the MRN complex, the ability of KAT5 to access H3K9me3 depends on the DNA damage-induced displacement of HP1beta (CBX1) from H3K9me3 (Ayoub et al. 2008). Binding to H3K9me3 activates the acetyltransferase activity of KAT5 (Sun et al. 2009). KAT5 acetylates ATM on lysine residue K3016 in the highly conserved C-terminal FATC domain of ATM. ATM acetylation is needed for the activation of ATM kinase activity in response to DNA damage (Sun et al. 2007).
R-HSA-5682586 (Reactome) PIAS4, an E3 SUMO ligase, is recruited to DNA double strand breaks (DSBs) via an unknown mechanism that requires a DNA-binding SAP domain of PIAS4 (Galanty et al. 2009). HERC2, an E3 ubiquitin ligase and a PIAS4 target, is recruited to DNA DSBs probably through its interaction with ATM (Bekker-Jensen et al. 2010).
R-HSA-5682588 (Reactome) RNF8 is an E3 ubiquitin ligase that, through its FHA domain, binds MDC1 phosphorylated at T-Q-X-F (Thr-Gln-X-Phe) sites by ATM. The phosphorylation of at least four T-Q-X-F sites of MDC1 (T699, T719, T752, T765) increases RNF8 binding to MDC1 (Kolas et al. 2007). RNF8 functions as a homodimer formed by interactions of the RNF8 coiled-coil domains (Cambell et al. 2012).
R-HSA-5682598 (Reactome) ATM phosphorylates HERC2 on threonine residue T4827. This threonine residue may also be phosphorylated by ATR and DNA-PKcs (PRKDC) (Bekker-Jensen et al. 2010).
R-HSA-5682607 (Reactome) PIAS4 SUMOylates HERC2 at an unknown lysine residue with SUMO1. ATM activity is needed for PIAS4-mediated HERC2 SUMOylation and it is therefore plausible that the ATM-mediated phosphorylation of HERC2 precedes HERC2 SUMOylation. Once SUMOylated, the ZZ domain of HERC2 interacts with the attached SUMO1 group, probably leading to a conformational change that allows binding of phosphorylated HERC2 to RNF8 (Bekker-Jensen et al. 2010, Danielsen et al. 2012).
R-HSA-5682629 (Reactome) HERC2 facilitates binding of the E2 ubiquitin conjugase dimer UBE2N:UBE2V2 (UBC13:MMS2) to RNF8 at DNA double strand breaks (DSBs) (Kolas et al. 2007, Bekker-Jensen et al. 2010, Campbell et al. 2012).
R-HSA-5682858 (Reactome) RNF8 and RNF168 E3 ubiquitin ligases work in concert with the E2 ubiquitin ligase complex UBE2N:UBE2V2 (UBC13:MMS2) to polyubiquitinate histone H2AFX (H2AX) on lysine residues K14 and K16 (commonly labeled in literature as K13 and K15) via ubiquitin lysine K63-directed cross-linking (Mattiroli et al. 2012). The scenario best supported by experimental evidence is that RNF8 initiates ubiquitination of H2AFX, followed by RNF168 binding to and extending ubiquitin chains ligated by RNF8 (Huen et al. 2007, Mailand et al. 2007, Stewart et al. 2009, Doil et al. 2009, Campbell et al. 2012).
R-HSA-5682863 (Reactome) The recruitment of RNF168, an E3 ubiquitin ligase, to DNA double strand breaks (DSBs) is facilitated by the interaction of RNF168 with the UBE2N:UBE2V2 (UBC13:MMS2) complex, which serves as the E2 ubiquitin ligase for both RNF8 and RNF168. In addition, because the two RNF168 ubiquitin interaction motifs (UIMs) are needed for the accumulation of RNF168 at DSBs, the initial ubiquitination of H2AFX (H2AX) histones by RNF8 is likely involved in RNF168 recruitment to DSBs. Inactivating mutations in both RNF168 alleles are responsible for the RIDDLE (radiosensitivity, immunodeficiency, dysmorphic features and learning difficulties) syndrome (Stewart et al. 2009, Doil et al. 2009, Bekker-Jensen et al. 2010, Campbell et al. 2012, Mattiroli et al. 2012).
R-HSA-5682965 (Reactome) WHSC1 (MMSET) histone methyltransferase dimethylates histone H4 (HIST1H4A) on lysine residue K21 (commonly labeled in literature as K20), locally increasing the concentration of the H4K20Me2 mark. H4K20Me2 (Me2-K21-HIST1H4A) serves as a binding site for TP53BP1 (53BP1). The recruitment of WHSC1 to DNA double strand breaks (DSBs) is independent of RNF8 and RNF168, but the catalytic activity of all three proteins is necessary for binding and accumulation of TP53BP1 at DSBs (Pei et al. 2011).
R-HSA-5682967 (Reactome) The histone methyltransferase WHSC1 (MMSET) is recruited to DNA double strand breaks (DSBs) likely through its interaction with histones and activated ATM (Pei et al. 2011).
R-HSA-5682983 (Reactome) Activated ATM phosphorylates WHSC1 (MMSET) on serine residue S102 (Matsuoka et al. 2007). The BRCT domain of MDC1 binds phosphorylated WHSC1, which is necessary for retention of WHSC1 at DNA double strand break (DSB) sites (Pei et al. 2011).
R-HSA-5682992 (Reactome) Histone demethylases KDM4A (JMJD2A) and KDM4B (JMJD2B) bind H4K20Me2 (Me2-K21-HIST1H4A) with a higher affinity than TP53BP1 (53BP1), thereby blocking TP53BP1 recruitment to DNA double strand breaks (DSBs). Demethylation of HIST1H4A (histone H4) by KDM4A or KDM4B is not involved in the inhibition of TP53BP1 binding (Mallette et al. 2012).
R-HSA-5683077 (Reactome) RNF8 and RNF168 polyubiquitinate KDM4A and KDM4B via ubiquitin lysine K48 cross-linking, leading to dissociation of ubiquitinated KDM4A and KDM4B from H4K20Me2 (Me2-K21-HIST1H4A) and subsequent proteasome-mediated degradation of KDM4A and KDM4B (Mallette et al. 2012).
R-HSA-5683384 (Reactome) UIMC1 (RAP80) is recruited to DNA double strand breaks (DSBs) through the interaction of its UIM (ubiquitin interaction motif) region with H2AFX (H2AX) ubiquitinated by RNF8 and RNF168 (Huen et al. 2007, Wang and Elledge 2007, Kolas et al. 2007, Mailand et al. 2007). A simultaneous interaction with FAM175A (Abraxas) through the AIR (Abraxas-interaction region) domain of UIMC1 facilitates UIMC1 binding to DNA DSBs. The interaction between UIMC1 and FAM175A and their loading to DNA DSBs is independent of BRCA1 (Wang et al. 2007, Wang and Elledge 2007).
R-HSA-5683385 (Reactome) A DNA damage-independent phosphorylation of FAM175A (Abraxas) serine residue S406 creates a pS-X-X-F (phospho-Ser-X-X-Phe) motif that binds BRCT repeats of BRCA1. The BRCA1 cancer predisposing mutation M1775R (Met1775Arg) inhibits BRCA1 binding to FAM175A. FAM175A interaction with UIMC1 (RAP80) enables BRCA1 recruitment to DNA double strand breaks (DSBs) (Wang et al. 2007). In addition to BRCA1, FAM175A also interacts with BRCC3 (BRCC36) (Wang et al. 2007, Hu et al. 2011) and BABAM1 (MERIT40, NBA1) (Vikrant et al. 2014). BABAM1 simultaneously interacts with BRE (BRCC45) (Hu et al. 2011). Together, BRCA1, BARD1, UIMC1, FAM175A, BRCC36, BRE and BABAM1 form the so-called BRCA1-A complex at DNA DSBs (Wang et al. 2009).
R-HSA-5683405 (Reactome) PPP5C-mediated dephosphorylation of TP53BP1 serine residues S25 and S1778 contributes to dissociation of TP53BP1 from DNA doubles strand break (DSB) sites and termination of DSB repair (Kang et al. 2009).
R-HSA-5683425 (Reactome) Activated ATM hyper-phosphorylates TP53BP1 (53BP1) at multiple residues in response to DNA damage (Fernandez-Capetillo et al. 2002, Ward et al. 2003, Jowsey et al. 2007). Phosphorylation of TP53BP1 serine residues S25 and S1778 is important for the retention of TP53BP1 at DNA double strand break (DSB) sites (Kang et al. 2009).
R-HSA-5683735 (Reactome) CHEK2 (CHK2, Cds1) is recruited to DNA double strand breaks (DSBs) mainly through its interaction with TP53BP1 (53BP1) (Wang et al. 2002), but BRCA1 also contributes to CHEK2 recruitment (Wilson and Stern 2008).
R-HSA-5683774 (Reactome) ATM-mediated phosphorylation of CHEK2 (CHK2, Cds1) on threonine residue T68 promotes formation of transitional CHEK2 homodimers primarily through intermolecular interactions of FHA domains and phospho-T68 residues of two CHEK2 protomers (Cai et al. 2009).
R-HSA-5683792 (Reactome) Upon dimerization, p-T68-CHEK2 protomers trans-autophosphorylate on serine residue S379 (Lovly et al. 2008) and threonine residues T383 and T387 (Lee et al. 2001). Autophosphorylation leads to dissociation of CHEK2 dimers into active CHEK2 monomers (Cai et al. 2009).
R-HSA-5683801 (Reactome) Activated CHEK2 phosphorylates BRCA1 on serine residue S988 (Lee et al. 2000), but does not phosphorylate BARD1, the heterodimerization partner of BRCA1 (Kim et al. 2006).
R-HSA-5683930 (Reactome) Under basal conditions, histone H2AFX (H2AX) is phosphorylated on tyrosine residue Y142 by the WICH complex composed of BAZ1B (WSTF) and SMARCA5 (SNF2H) (Xiao et al. 2009).
R-HSA-5683964 (Reactome) EYA tyrosine protein phosphatases (EYA1, EYA2 and EYA3) play an important role in repair of DNA double strand breaks (DSBs) (Cook et al. 2009, Krishnan et al. 2009). The role of EYA4 in the context of DNA damage has not been examined but is plausible based on sequence similarity. EYA3 is phosphorylated by activated ATM on serine residue S266 (labeled as S219 by Cook et al. 2009) and this phosphorylation is important for the catalytic activity of EYA3 (Cook et al. 2009). Although EYA1, EYA2 and EYA4 possess several sites that match the ATM consensus SQ/TQ sequence, their phosphorylation by ATM has not been examined
R-HSA-5683967 (Reactome) In response to DNA damage, EYA tyrosine protein phosphatases (EYA1, EYA2, EYA3 and, by sequence similarity, EYA4) dephosphorylate tyrosine Y142 of H2AFX, which allows the progression of DNA repair (Cook et al. 2009, Krishnan et al. 2009). It is possible that different EYA proteins heterodimerize in different cell types - the existence of a functional EYA1:EYA3 heterodimer in human embryonic kidney 293 (HEK293) cells is likely (Cook et al. 2009).

MCPH1 recognizes and binds diphosphorylated H2AFX, but the exact biological role of this interaction has not been elucidated (Singh et al. 2012).

R-HSA-5683986 (Reactome) In the absence of sufficient EYA1-4 activity, APBB1 (FE65) binds diphosphorylated H2AFX and recruits MAPK8 (JNK1) to H2AFX. This triggers pro-apoptotic signaling and targets the affected cell for apoptosis instead of DNA repair (Cook et al. 2009).
R-HSA-5684006 (Reactome) KPNA2 facilitates the translocation of NBN (NBS1) to the nucleus, thereby making NBN available for the formation of MRN complexes in response to DNA double strand breaks (DSBs) (Tseng et al. 2005).
R-HSA-5684008 (Reactome) In the cytosol, NBN (NBS1) binds KPNA2, an importin alpha family member. The armadillo repeats of KPNA2 and a nuclear localization signal (NLS) of NBN are involved in the interaction (Tseng et al. 2005).
R-HSA-5686578 (Reactome) ATM, activated in response to DNA damage in the form of double strand breaks, phosphorylates ABL1 (c-ABL) on serine residue S456, resulting in the activation of kinase activity of ABL1 (Baskaran et al. 1997).
R-HSA-5693536 (Reactome) The function of MDC1 in recruiting and retaining DNA repair proteins at the sites of DNA damage (Xu and Stern 2003, Stewart et al. 2003) is promoted by the ATM-mediated phosphorylation of MDC1 (Liu et al. 2012). Phosphorylation of MDC1 (NFBD1) by ATM at threonine residue T4 stabilizes otherwise unstable MDC1 homodimers by enabling in trans interaction of MDC1 FHA domains with phosphorylated N-terminal threonine residues (Goldberg et al. 2003, Liu et al. 2012). ATM also phosphorylates MDC1 on at least four threonine residues that match the consensus RNF8-binding sequence T-Q-X-F: T699, T719, T752, T765 (Kolas et al. 2007). Binding of the ubiquitin ligase RNF8 to ATM phosphorylated MDC1 is necessary for the recruitment of TP53BP1 and BRCA1 to DNA double strand break (DSB) sites.
R-HSA-5693540 (Reactome) MRN promotes dissociation of ATM dimers to ATM monomers which is accompanied by ATM trans-autophosphorylation on serine residue S1981 (Bakkenist et al. 2003, Du et al. 2014). ATM autophosphorylation at serine residues S367 and S1893 is also implicated in ATM activation (Kozlov et al. 2006). Dissociation of ATM dimers requires the ATP-dependent DNA-helicase activity of the MRN subunit RAD50 (Lee and Paull 2005). KAT5 (Tip60) mediated acetylation of ATM dimers at lysine K3016 is a prerequisite for ATM kinase activity (Sun et al. 2007). Upon the dissociation of ATM dimers induced by DNA double strand breaks (DSBs), a fraction of activated ATM is retained at DSB sites, co-localizing with the MRN complex (Andegeko et al. 2001, Uziel et al. 2003) at ionizing radiation-induced foci (IRIF). MRN facilitates the binding of a portion of ATM substrates to ATM (Lee and Paull 2004).

After the DNA double strand breaks (DSBs) are repaired, ATM is dephosphorylated by an unidentified PP2A phosphatase complex, leading to dimer reformation (Goodarzi et al. 2004).

R-HSA-5693549 (Reactome) ATM phosphorylates histone H2AFX (H2AX) on serine S139 within 1-3 minutes of double strand break (DSB) formation, producing gamma-H2AX (gamma-H2AFX) (Rogakou et al.1998, Burma et al. 2001). Basal phosphorylation of H2AFX on tyrosine residue Y142 contributes to successful S139 phosphorylation and results in a transient diphosphorylated H2AFX (Cook et al. 2009). Gamma-H2AFX localizes to a region of about 2 Mbp surrounding the site of the DSB (Rogakou et al.1998), playing an essential role in the stable recruitment of other repair proteins and formation of ionizing radiation-induced foci (IRIF) at DSB sites (Paull et al. 2000, Celeste et al. 2002, Celeste et al. 2003, Stewart et al., 2003). Recruitment of MDC1 to gamma-H2AFX may be important for the sustained phosphorylation of H2AFX at DSBs (Stewart et al. 2003).
R-HSA-5693551 (Reactome) ATM phosphorylates BRCA1 at serine residues S1387, S1423, S1524 and S1547 (Cortez et al. 1999, Gatei et al. 2000). At least a fraction of these sites and some additional BRCA1 SQ/TQ sites can also be phosphorylated by ATR (Tibbetts et al. 2000). ATM also phosphorylates BARD1, the heterodimerization partner of BRCA1, at threonine residues T714 and T734 (Kim et al. 2006).
R-HSA-5693566 (Reactome) RNF8- and RNF168-mediated removal of KDM4A and KDM4B from H4K20Me2 (Me2-K21-HIST1H4A) enables TP53BP1 (53BP1) recruitment to WHSC1-methylated histone H4K20Me2 at DNA double strand breaks (DSBs) (Pei et al. 2011, Mallette et al. 2012)
R-HSA-5693583 (Reactome) Recruitment of MDC1 to nuclear foci (IRIF - ionizing radiation induced foci) is mediated by phosphorylated H2AFX (gamma-H2AX, gamma-H2AFX). Once bound, MDC1 promotes sustained phosphorylation of H2AFX by enhancing the interaction between ATM and H2AFX. The BRCT domain of MDC1 binds gamma-H2AFX, while the FHA domain of MDC1 interacts with ATM. Thus, ATM, H2AFX and MDC1 form a positive feedback loop that amplifies downstream ATM signaling and phosphorylation of other ATM targets (Goldberg et al. 2003, Stewart et al. 2003, Stucki et al. 2005, Lou et al. 2006). MDC1 also binds NBN (NBS1) component of the MRN complex, serving as a molecular linker between the MRN complex and the ATM-phosphorylated H2AFX. Although the initial recruitment of the MRN complex to DNA double strand breaks (DSBs) and ATM-mediated phosphorylation of NBN do not depend on MDC1, MDC1 is necessary for the retention of the MRN complex at DSB sites (Lukas et al. 2004).
R-HSA-5693598 (Reactome) NSB1 (NBN) is a component of the MRN (MRE11:RAD50:NBN) complex which acts early in homologous recombination repair (HRR) during recognition and resection of double-strand breaks (DSBs). ATM-mediated phosphorylation of NBN at serine residue S343 is required for activation of the S-phase checkpoint in response to ionizing radiation (IR), ATM-dependent activation of CHK2 and cell survival after exposure to IR (Lim et al. 2000, Gatei et al. 2000, Lee and Paull 2004). The phosphorylation of NBN by ATM may be enhanced by the presence of BRCA1 (Foray et al. 2003).
R-HSA-5693602 (Reactome) H2AFX (also known as H2AX) is a variant of histone H2A and is present in a portion of nucleosomes. While H2AFX-containing nucleosomes (H2AFX-nucleosomes) are not specifically recruited to the sites of DNA double strand breaks (DSBs), ATM recognizes the carboxyl tails of H2AFX on H2AFX-nucleosomes in the vicinity of DSBs as a suitable phosphorylation substrate. The phosphorylated H2AFX (gamma-H2AX) plays a crucial role in the retention of DNA repair proteins at DSBs, manifested in the formation of ionizing radiation-induced foci (Paull et al. 2000, Celeste et al. 2002, Redon et al. 2002, Celeste et al. 2003, Fernandez-Capetillo et al. 2004).
R-HSA-5693609 (Reactome) In response to DNA double strand breaks, serine at position 15 of the TP53 (p53) tumor suppressor protein is rapidly phosphorylated by the ATM kinase. This serves to stabilize the p53 protein. A rise in the levels of the p53 protein induces the expression of p21 cyclin-dependent kinase inhibitor. This prevents the normal progression from G1 to S phase, thus providing a check on replication of damaged DNA (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998).
R-HSA-5693612 (Reactome) Activation of ATM kinase in response to DNA damage in the form of DNA double strand breaks (DSBs) requires association of ATM dimers with the MRN complex bound to DNA ends. MRN subunit RAD50 is essential for ATM dimer binding (Lee and Paull 2005, Wu et al. 2007). ATM dimer exists in a preformed complex with KAT5 (Tip60) histone acetyltransferase (Sun et al. 2005).
R-HSA-69891 (Reactome) Activated ATM phosphorylates CHEK2 (CHK2, Cds1) on threonine residue T68 (Matsuoka et al. 2000, Melchionna et al. 2000). The presence of BRCA1 and TP53BP1 positively regulates ATM-mediated phosphorylation of CHEK2 (Wang et al. 2002, Foray et al. 2003). ATM-mediated phosphorylation causes formation of CHEK2 dimers and dissociation of CHEK2 from chromatin (Li and Stern 2005).
R-HSA-75172 (Reactome) MRE11 has both manganese dependent ssDNA 3'->5' exonuclease and endonuclease activities. MRE11 associates with RAD50, resulting in increased 3'-5' exonuclease activity (Dolganov et al. 1996, Paull and Gellert 1998).
R-HSA-75174 (Reactome) NBN (NBS1) binds MRE11A:RAD50 complex to form the evolutionarily conserved MRN complex (Trujillo et al. 1998).
RAD50:MRE11AArrowR-HSA-75172 (Reactome)
RAD50:MRE11AR-HSA-75174 (Reactome)
RAD50R-HSA-75172 (Reactome)
RNF168R-HSA-5682863 (Reactome)
RNF8:Zn2+R-HSA-5682588 (Reactome)
SUMO1:C93-UBE2IR-HSA-5682607 (Reactome)
TP53 TetramerR-HSA-5693609 (Reactome)
TP53BP1R-HSA-5693566 (Reactome)
UBE2IArrowR-HSA-5682607 (Reactome)
UBE2N:UBE2V2R-HSA-5682629 (Reactome)
UIMC1R-HSA-5683384 (Reactome)
UbR-HSA-5682858 (Reactome)
UbR-HSA-5683077 (Reactome)
WHSC1R-HSA-5682967 (Reactome)
WICHmim-catalysisR-HSA-5683930 (Reactome)
dsDNAR-HSA-3785704 (Reactome)
p-EYA1-4ArrowR-HSA-5683964 (Reactome)
p-EYA1-4mim-catalysisR-HSA-5683967 (Reactome)
p-S,3T-CHEK2ArrowR-HSA-5683792 (Reactome)
p-S,3T-CHEK2mim-catalysisR-HSA-5683801 (Reactome)
p-S15-TP53 TetramerArrowR-HSA-5693609 (Reactome)
p-S1981,Ac-K3016-ATMArrowR-HSA-5693540 (Reactome)
p-S1981,Ac-K3016-ATMmim-catalysisR-HSA-5686578 (Reactome)
p-S1981,Ac-K3016-ATMmim-catalysisR-HSA-5693609 (Reactome)
p-S406-FAM175AR-HSA-5683384 (Reactome)
p-S456-ABL1ArrowR-HSA-5686578 (Reactome)
p-T,Y-MAPK8R-HSA-5683986 (Reactome)
p-T68-CHEK2 dimerArrowR-HSA-5683774 (Reactome)
p-T68-CHEK2 dimerR-HSA-5683792 (Reactome)
p-T68-CHEK2 dimermim-catalysisR-HSA-5683792 (Reactome)
p-T68-CHEK2ArrowR-HSA-69891 (Reactome)
p-T68-CHEK2R-HSA-5683774 (Reactome)
p-Y142-H2AFX-NucleosomeArrowR-HSA-5683930 (Reactome)
p-Y142-H2AFX-NucleosomeR-HSA-5693602 (Reactome)
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