DNA Double Strand Break Response (Homo sapiens)

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1059342, 58, 75, 909130, 55, 60, 68, 1203344, 601047, 9111, 34, 39, 41, 104...25, 49, 8718, 44, 61, 68, 120...3, 8, 9, 13, 17...22, 902, 10, 36, 45, 59...15, 19, 21, 46, 10291767, 79, 10429, 7177, 95, 10930, 94, 99, 11718, 44, 61, 93, 121724, 60, 646, 9311628, 86, 11635, 9151, 98, 109, 11010011, 34, 39, 66, 10337, 48, 50, 7092, 11115, 633332, 53, 64, 78, 10179, 104378044, 60, 9321, 73, 81, 11523, 9356, 77, 11240nucleoplasmcytosolUBC(533-608) DNA double-strandbreak endsMe2K21-HIST1H4 Me2K21-HIST1H4 EYA2 UBE2V2 EYA1 p-S1981,Ac-K3016-ATM MRE11A UBC(1-76) ATPDNA double-strand break ends K63PolyUb-K14,K16,p-S139-H2AFX MRE11A Zn2+ KDM4A APBB1ADPDNA double-strand break ends DNA double-strand break ends RAD50 p-5T-MDC1 K63PolyUb-K14,K16,p-S139-H2AFX HIST2H2BE HIST2H2BE HIST1H2BL HIST1H2BL MRE11A HIST1H2BH p-EYA4 HIST3H3 UBB(77-152) EYA3 HIST3H2BB MRE11A RAD50 ATPHIST1H2BO HIST2H2BE HIST1H2BM HIST3H3 HIST1H2BB RNF8 p-S343-NBN HIST3H3 HIST1H4 p-T4827,SUMO1-HERC2 Me2K21-HIST1H4 HIST1H2BL Me2K21-HIST1H4 HIST1H2BN H2BFS HIST1H2BD RAD50 HIST1H2BO HIST1H2BA UBE2V2 p-T68-CHEK2KDM4B HIST2H2BE HIST1H2BC KAT5 EYA4 HERC2-SUMO1 BABAM1UBE2V2 HIST1H2BO HIST2H2BE KAT5 DNA double-strand break ends UIMC1 NBN Zn2+ DNA double-strand break ends HIST1H2BK p-S343-NBN p-S1981,Ac-K3016-ATM p-5T-MDC1 HIST1H2BM HIST3H2BB HIST1H2BL HIST1H2BK HERC2-SUMO1 HIST1H2BO DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1:p-S102-WHSC1HIST1H2BD HIST1H2BK p-S139-H2AFX HIST1H2BA HIST3H3 Zn2+ HIST1H2BJ HIST1H2BO HIST1H2BA KAT5 HIST3H2BB HIST1H2BC DNA double-strand break ends RNF8 UBE2V2 HIST2H2BE DNA double-strand break ends HIST1H2BN HIST3H3 p-5T-MDC1 p-S102-WHSC1 HIST2H2BE H2BFS HIST1H2BO HIST1H2BO KPNA2p-5T-MDC1 HERC2-SUMO1 RNF168 HIST1H2BK Me2K21-HIST1H4 PIAS4 HIST1H2BO p-5T-MDC1 MRE11A KAT5 p-Y142-H2AFX-NucleosomeKAT5 MRE11A KAT5 UBE2N:UBE2V2KAT5 gamma-ray HIST1H2BL KAT5 PIAS4 HIST1H2BK p-S1981,Ac-K3016-ATM p-5T-MDC1 HIST1H4 HIST1H2BO HIST1H2BB UBE2N BABAM1 MRE11A HIST1H2BO HIST1H2BH RNF168 p-S139-H2AFX p-S1981,Ac-K3016-ATM HIST1H2BL p-S343-NBN p-EYA2 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:PIAS4HIST1H2BD UBE2N HIST2H2BE HIST1H2BB H2BFS p-S1981,Ac-K3016-ATM MDC1 RAD50 HIST3H3 p-S1981,Ac-K3016-ATM KDM4B NBN UBE2N ROS HIST1H2BJ HIST2H2BE ATM HIST3H3 HIST3H2BB BRCA1 ADPUBB(1-76) Me2K21-HIST1H4 HIST1H4 H2BFS HIST1H2BO HIST1H2BK HIST1H2BC Zn2+ HERC2-SUMO1 CHEK2p-S343-NBN HIST1H2BL HIST1H2BA RAD50 p-S102-WHSC1 HIST1H2BJ HIST1H2BK HIST1H2BN RNF8:Zn2+HERC2-SUMO1 CoA-SHHIST1H2BD HIST1H4 RAD50 UBC(609-684) HIST1H2BA RAD50 p-5T-MDC1 DNA double-strand break ends HIST1H2BH HIST1H2BM HIST1H4 HIST1H2BA HIST1H2BH HIST1H2BA p-S343-NBN HIST3H3 KDM4B RNF8 HIST1H2BN p-5T-MDC1 K63PolyUb-K14,K16,p-S139-H2AFX HIST1H2BD HIST1H2BL UBE2V2 p-S456-ABL1HIST1H2BL p-Y142-H2AFX HIST1H2BA HIST1H2BK p-S343-NBN Zn2+ p-S1981,Ac-K3016-ATM K48PolyUb-KDM4A,BUBE2N p-S102-WHSC1 HIST1H2BA HIST1H2BJ HIST2H2BE HIST1H2BM HIST3H2BB HIST1H2BB p-S343-NBN RNF8 HIST1H2BL HIST1H2BO HIST3H2BB MRNDNADNADSBs: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-FAM175ARAD50 HIST1H2BH HIST1H2BC HIST1H2BD H2BFS p-T68-CHEK2 HIST2H2BE HIST2H2BE DNA double-strand break ends H2BFS 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+KAT5 HERC2-SUMO1 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:PIAS4UBE2V2 PiHIST1H2BM KAT5 HIST1H2BL HERC2 p-S1981,Ac-K3016-ATM p-S1981,Ac-K3016-ATM BARD1HIST1H2BA HIST1H2BH HIST1H2BH HDR through MMEJ(alt-NHEJ)HIST1H2BC NBN:KPNA2RAD50 UBE2N HIST1H2BN HIST1H2BC K63PolyUb-K14,K16,p-S139-H2AFX Me2K21-HIST1H4 BRCC3 KPNA2 Me2K21-HIST1H4 DNA double-strand break ends p-S1981,Ac-K3016-ATM Ac-CoAHIST1H2BL Me2K21-HIST1H4 H2BFS HIST3H3 HIST1H2BK RNF168 NonhomologousEnd-Joining (NHEJ)HIST1H2BD MRE11A KDM4B HIST1H2BO HIST1H2BO p-S1981,Ac-K3016-ATM MDC1p-5T-MDC1 HIST1H2BC MRE11A KDM4B HIST1H2BL SUMO1-C93-UBE2I DNA double-strand break ends HIST1H2BM RNF8 HIST1H2BL KDM4A HIST1H2BM RAD50 KDM4A HIST1H2BH KDM4A HIST1H2BM PPP5CH2BFS HIST1H2BJ HIST1H2BN DSB inducing agentsp-T4827,SUMO1-HERC2 HIST1H2BC HIST1H2BM KAT5 AdoMetp-S102-WHSC1 p-S25,S1778-TP53BP1 HIST2H2BE HIST3H2BB HIST1H2BA HIST1H2BH HIST1H2BO BRCA1HIST3H3 DNA DSBs:MRNUBE2V2 p-S1981,Ac-K3016-ATM UBE2V2 TP53 HIST1H2BA MRE11A KDM4A MRE11A HIST1H4 p-T4827,SUMO1-HERC2 ADPATPHIST1H2BH HIST1H2BH DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139,Y142-H2AFX-NucleosomeUIMC1 p-S102-WHSC1 HIST1H2BL HIST1H2BJ HIST1H2BN HIST1H2BJ PIAS4 HIST1H2BB p-S1387,S1423,S1524,S1547-BRCA1 RNF8 KDM4A H2BFS HIST1H2BA HIST1H2BK H2BFS HIST1H2BL PIAS4 HIST1H2BL RAD50 MRE11A HIST1H2BH RNF168 HIST1H2BC HIST1H2BN KAT5 BABAM1 RNF8 RAD50 HIST1H2BJ PIAS4 p-S1981,Ac-K3016-ATM HIST1H2BK H2BFS KDM4B HIST2H2BE p-S25,S1778-TP53BP1 UBE2N KDM4A,BHIST1H2BC HIST1H2BA DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139,Y142-H2AFX-Nucleosome:APBB1:p-T,Y-MAPK8HIST3H2BB HIST1H2BC KAT5 HIST1H2BN HIST2H2BE H2BFS HIST1H2BN HIST1H2BJ HIST1H2BN MRE11A p-S1981,Ac-K3016-ATM KAT5 p-S1981,Ac-K3016-ATMAPBB1 HIST1H2BD DNA DSBs:MRN:ATMdimer:KAT5DNA double-strand break ends ATPUBC(153-228) BABAM1 HIST1H2BB ATPPiBRCC3 HIST1H2BB p-S102-WHSC1 UBE2N p-T4827,SUMO1-HERC2 UIMC1HIST1H2BJ HIST1H2BN HIST1H2BJ 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:TP53BP1HIST3H2BB HIST2H2BE BRCA1:BARD1ATM p-5T-MDC1 HIST3H2BB HIST1H2BM HIST1H2BD KAT5 PIAS4 DNA double-strand break ends ADPABL1MRE11A 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:PIAS4HIST1H2BD HIST1H2BJ HIST3H3 p-S139-H2AFX DNA double-strand break ends KAT5 ATPKAT5 RNF8 HIST1H2BN RAD50 HIST1H2BN HIST1H2BB HIST1H2BK KAT5 BRCA1 Me2K21-HIST1H4 ATPp-S139-H2AFX BRCC3UBE2V2 DNA double-strand break ends dsDNAHIST3H2BB HIST1H2BM HIST1H2BN HIST1H2BK HIST1H2BO 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 complexRAD50 TP53BP1p-5T-MDC1 HIST1H2BL HIST1H2BD p-S343-NBN DNA double-strand break ends EYA1-4H2BFS HIST1H2BM p-S343-NBN UBE2N RNF168 RAD50 NBNRAD50HIST1H2BL ADPHIST2H2BE MRE11A HIST1H2BA KDM4B KAT5 WHSC1 HIST1H2BH BRCC3 HIST1H2BB p-S343-NBN PIAS4 HIST1H2BC HIST3H3 p-S343-NBN p-S25,S1778-TP53BP1 HIST1H2BM HIST1H2BB p-5T-MDC1 UBE2V2 p-5T-MDC1 Zn2+ H2BFS CHEK2 HIST1H2BJ HIST1H2BK p-EYA1-4UBE2V2 HIST3H3 p-T4827,SUMO1-HERC2 HIST1H2BC p-S1981,Ac-K3016-ATM HIST1H2BD HIST1H2BH TP53 TetramerHIST3H3 H2BFS HIST1H2BC MRE11A KAT5 ATM dimer:KAT5UIMC1 p-S139-H2AFX ADPHIST1H2BJ SMARCA5 p-S343-NBN ADPHIST1H2BN KPNA2p-S1981,Ac-K3016-ATM PIAS4 UIMC1 HIST3H3 HIST1H2BO HIST1H2BN DNA double-strand break ends HIST1H2BM HIST1H2BH MRE11A p-S102-WHSC1 HIST1H2BN HIST3H2BB HIST1H2BH Zn2+ Zn2+ MRE11A p-S139-H2AFX HIST1H2BM p-T,Y-MAPK8BRE UIMC1 HIST1H2BL HIST1H2BL HIST1H2BL ATPHIST1H2BJ p-S102-WHSC1 HIST1H2BD p-EYA1 HIST1H2BC HIST1H2BA RAD50 DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:MDC1HIST3H2BB HERC2-SUMO1 HIST1H2BO HIST1H2BN HIST1H2BJ MRE11A HIST1H2BD p-S139-H2AFX HIST1H2BM HIST1H2BM ADPHIST1H2BL Zn2+ HIST1H2BB KAT5 HIST2H2BE p-S343-NBN p-S102-WHSC1 HIST1H2BJ HIST1H2BC p-S1981,Ac-K3016-ATM 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:PIAS4p-S406-FAM175A HIST1H2BD HIST3H3 HIST1H2BA KAT5 H2AFX HERC2alpha-particle RAD50 PIAS4 HIST1H2BB HIST1H2BO H2BFS HIST1H2BK HIST3H2BB KAT5 HIST3H2BB p-S139-H2AFX HIST1H2BB HIST3H3 p-5T-MDC1 p-S102-WHSC1 p-S406-FAM175AHIST1H2BD p-5T-MDC1 PIAS4 HIST1H2BC HIST1H2BA HIST1H2BD HIST1H2BA HIST1H2BB Me2K21-HIST1H4 HIST3H3 p-T714,T734-BARD1 HIST1H2BH PIAS4 HIST2H2BE HERC2-SUMO1 HIST3H3 p-S15-TP53 HIST1H2BK BABAM1 p-S343-NBN RAD50 p-S406-FAM175A HIST1H2BC p-S102-WHSC1 HIST1H2BK HIST1H2BK HIST3H2BB DNA double-strand break ends HIST3H2BB HIST1H2BN HIST1H2BB ATPp-S139,Y142-H2AFX KAT5 p-S102-WHSC1 p-S139-H2AFX p-5T-MDC1 p-T4827,SUMO1-HERC2 Me2K21-HIST1H4 HIST1H2BJ HIST1H2BM p-5T-MDC1 HIST1H2BL KDM4B PIAS4HIST1H2BJ HIST1H2BH MRE11A KDM4A NBNp-S25,S1778-TP53BP1 MRE11A DNA double-strand break ends RAD50 HIST1H2BD HIST1H2BD HIST1H2BH HIST1H2BO DNA double-strand break ends HIST1H2BH HIST1H2BO RAD50:MRE11 complexBREp-S1981,Ac-K3016-ATM HIST3H2BB HIST1H2BD HIST1H2BB RAD50 p-S139-H2AFX H2BFS HIST1H2BJ 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:CHEK2p-S1981,Ac-K3016-ATM p-T4827,SUMO1-HERC2 DNA double-strand break ends NBN p-S25,S1778-TP53BP1 MRE11Aproton NBN DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-NucleosomeHIST1H2BN p-S1387,S1423,S1524,S1547-BRCA1 MRE11A UBC(77-152) ATPZn2+ p-Y142-H2AFX p-T4827,SUMO1-HERC2 p-5T-MDC1 K48PolyUb-KDM4A HIST3H3 HIST1H2BM p-S343-NBN HIST1H2BM p-S102-WHSC1 BARD1 HIST3H3 KAT5 Me2K21-HIST1H4 RAD50 DNA double-strand break ends MRE11A RNF8 RAD50 DNADSB:p-MRN:p-S1981,Ac-K3016-ATM:KAT5ADPHIST1H2BA RAD50 HIST3H2BB HIST2H2BE K63PolyUb-K14,K16,p-S139-H2AFX p-T4827,SUMO1-HERC2 HIST1H2BJ p-S1981,Ac-K3016-ATM HIST2H2BE Ac-K3016-ATM SUMO1:C93-UBE2IDNA double-strand break ends RNF8 BAZ1B RNF168DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1DNA double-strand break ends HIST1H2BN 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:PIAS4HDR throughHomologousRecombination (HR)or Single StrandAnnealing (SSA)HIST1H2BK HIST1H2BB MRE11A Zn2+ HIST1H2BJ KDM4A p-S102-WHSC1 p-S1981,Ac-K3016-ATM p-T714,T734-BARD1 p-T,Y-MAPK8 p-S102-WHSC1 BARD1 p-T4827,SUMO1-HERC2 WHSC1HIST3H3 RAD50 RNF8 Me2K21-HIST1H4 HIST1H2BD p-S1981,Ac-K3016-ATM p-S15-TP53 TetramerHIST1H2BK HIST1H2BN DNA double-strand break ends MRE11A Zn2+ KDM4A BRE HIST1H2BH p-S343-NBN H2BFS HIST1H2BM HIST1H2BB Zn2+ RNF8 ADPHIST1H2BM HIST1H2BM HIST3H3 HIST3H2BB K63PolyUb-K14,K16,p-S139-H2AFX HIST1H2BA H2BFS ATPHIST1H2BB Me2K21-HIST1H4 DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX-Nucleosome:p-5T-MDC1:WHSC1PIAS4 p-5T-MDC1 p-S,3T-CHEK2DNADSBs:p-MRN:p-S-1981,Ac-K3016-ATM:KAT5:p-Y142-H2AFX-Nucleosomep-EYA3 HIST1H2BC HIST2H2BE HIST1H2BM KDM4B HIST1H2BK RAD50 RNF8 p-S988,S1387,S1423,S1524,S1547-BRCA1 HIST1H2BN HIST1H2BB ubiquitinHIST1H2BB p-S406-FAM175A Me2K21-HIST1H4 p-S1981,Ac-K3016-ATM p-S139,Y142-H2AFX BRE HIST1H2BO p-T714,T734-BARD1 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:PIAS4HIST1H4 p-S406-FAM175A HIST1H2BK DNA double-strand break ends RNF168 RAD50 HIST1H2BB HIST1H2BJ HIST1H2BB p-S139-H2AFX H2AFX-NucleosomeZn2+ ATPMRE11A p-T4827-HERC2 p-S1981,Ac-K3016-ATM WICHDNADNADSBs: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 complexHIST1H2BN p-S343-NBN beta-particle DNADSBs:MRN:p-S1981,Ac-K3016-ATM:KAT5KAT5 p-S25,S1778-TP53BP1 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-TP53BP1HIST1H2BO HIST1H2BB RNF8 RAD50 ATPHIST1H2BO HIST1H2BC p-S343-NBN HIST1H2BH DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1RAD50 p-T68-CHEK2 dimerp-S343-NBN H2BFS HIST1H2BO RNF8 HERC2-SUMO1 HIST1H2BC DNA double-strand break ends HIST1H2BA RNF168 HIST1H2BC HIST1H2BL H2BFS HIST1H2BK HIST1H2BO HIST1H2BD UBC(457-532) HIST1H4 HIST1H2BJ p-S1981,Ac-K3016-ATM TP53BP1 DNADSBs:MRN:Ac-K3016-ATM dimer:KAT5HIST1H2BM RAD50 HIST3H3 p-S343-NBN HIST3H2BB HIST1H2BK KAT5 PIAS4 HIST1H2BM HIST1H2BO BRE MRE11A H2BFS HIST1H2BM HIST2H2BE p-S1981,Ac-K3016-ATM UBC(229-304) HIST1H2BB p-T4827,SUMO1-HERC2 HIST1H2BL UBE2IHIST2H2BE HIST1H2BC MDC1 ADPHIST1H2BC HIST3H3 H2BFS UBE2N HIST3H2BB p-S343-NBN UBA52(1-76) H2OHIST1H2BB HIST1H4 ATPDNADSBs: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:PIAS4DNADNADSBs: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 complexMe2K21-HIST1H4 Zn2+ RNF168 HERC2-SUMO1 HIST1H2BN H2BFS p-S102-WHSC1 HIST1H2BC KAT5 HIST1H2BA HERC2-SUMO1 p-S139-H2AFX DNA double-strand break ends HIST1H2BH HIST1H2BH p-5T-MDC1 MRE11A HIST3H3 UBE2I-G97-SUMO1 HIST3H2BB p-S102-WHSC1 ATPHIST2H2BE p-S102-WHSC1 AdoHcyUBC(381-456) HIST1H2BB HIST1H2BK HIST1H2BJ K48PolyUb-KDM4B DNA double-strand break ends UBE2N H2OHIST1H2BN HIST1H4 UBE2V2 DNADSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1HIST3H2BB BRCC3 Zn2+ HIST1H2BD RAD50 HERC2-SUMO1 HIST3H2BB H2BFS p-S343-NBN H2BFS ADPp-S343-NBN K63PolyUb-K14,K16,p-S139-H2AFX HIST1H2BK RPS27A(1-76) K63PolyUb-K14,K16,p-S139-H2AFX HIST1H2BH RAD50 MRE11A HIST1H2BL KAT5 HIST3H3 MRE11A p-S406-FAM175A HIST1H2BD RAD50 p-S1981,Ac-K3016-ATM NBN HIST2H2BE K63PolyUb-K14,K16,p-S139-H2AFX HIST3H2BB DNA double-strand break ends ADPHIST1H2BA p-T4827,SUMO1-HERC2 HIST1H2BD HIST1H2BD NBN HIST1H2BJ HIST1H2BD ADPMRE11A UBE2N p-S343-NBN UBC(305-380) HIST1H2BJ HIST1H2BA HIST1H2BC X-ray HIST1H2BC p-S139-H2AFX MRE11A RNF168 ADPHIST1H2BA UBB(153-228) HIST1H2BH p-S343-NBN UBE2N HIST1H2BK HIST1H2BA RNF8 p-S343-NBN KAT5 RNF168 PIAS4 H2BFS HIST3H2BB HIST2H2BE 91109660606666963030597, 914, 5, 7, 11, 14...6669177, 953365307766667, 91301041, 12, 26, 27, 57...116615, 6366105791


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.

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Bibliography

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  91. Bakkenist CJ, Kastan MB.; ''DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.''; PubMed Europe PMC Scholia
  92. Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM.; ''A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage.''; PubMed Europe PMC Scholia
  93. 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
  94. Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B, Petalcorin MI, O'Connor KW, Konstantinopoulos PA, Elledge SJ, Boulton SJ, Yusufzai T, D'Andrea AD.; ''Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair.''; PubMed Europe PMC Scholia
  95. Kim HS, Li H, Cevher M, Parmelee A, Fonseca D, Kleiman FE, Lee SB.; ''DNA damage-induced BARD1 phosphorylation is critical for the inhibition of messenger RNA processing by BRCA1/BARD1 complex.''; PubMed Europe PMC Scholia
  96. Andegeko Y, Moyal L, Mittelman L, Tsarfaty I, Shiloh Y, Rotman G.; ''Nuclear retention of ATM at sites of DNA double strand breaks.''; PubMed Europe PMC Scholia
  97. Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC.; ''Homology and enzymatic requirements of microhomology-dependent alternative end joining.''; PubMed Europe PMC Scholia
  98. Singh N, Basnet H, Wiltshire TD, Mohammad DH, Thompson JR, Héroux A, Botuyan MV, Yaffe MB, Couch FJ, Rosenfeld MG, Mer G.; ''Dual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1.''; PubMed Europe PMC Scholia
  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
  100. Lee JS, Collins KM, Brown AL, Lee CH, Chung JH.; ''hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response.''; PubMed Europe PMC Scholia
  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

View all...
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)
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-NUL-75165 (Reactome)
DNA double-strand break ends R-NUL-75165 (Reactome)
DSB inducing agentsComplexR-HSA-R-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 (HR) 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-S139-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:MRE11 complexComplexR-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)
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-S139,Y142-H2AFX ProteinP16104 (Uniprot-TrEMBL)
p-S139-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 ProteinP16104 (Uniprot-TrEMBL)
p-Y142-H2AFX-NucleosomeComplexR-HSA-5683932 (Reactome)
proton MetaboliteCHEBI:24636 (ChEBI)
ubiquitinComplexR-HSA-68524 (Reactome)

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-5693577 (Reactome)
ADPArrowR-HSA-5693598 (Reactome)
ADPArrowR-HSA-5693609 (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-5693577 (Reactome)
ATPR-HSA-5693598 (Reactome)
ATPR-HSA-5693609 (Reactome)
Ac-CoAR-HSA-5682044 (Reactome)
AdoHcyArrowR-HSA-5682965 (Reactome)
AdoMetR-HSA-5682965 (Reactome)
BABAM1R-HSA-5683385 (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-5693577 (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-5693577 (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-5693577 (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-5693577 (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-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-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:MRE11 complexArrowR-HSA-75172 (Reactome)
RAD50:MRE11 complexR-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)
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-5693577 (Reactome)
p-T68-CHEK2R-HSA-5683774 (Reactome)
p-Y142-H2AFX-NucleosomeArrowR-HSA-5683930 (Reactome)
p-Y142-H2AFX-NucleosomeR-HSA-5693602 (Reactome)
ubiquitinR-HSA-5682858 (Reactome)
ubiquitinR-HSA-5683077 (Reactome)
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