Nonhomologous End-Joining (Homo sapiens)

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1, 3, 5-7, 9...10, 21, 48, 50, 5327, 40, 41, 49, 559, 13, 22, 24, 2823, 496, 36, 581, 12, 14, 17, 21...2, 4, 3216, 23, 4732, 3311, 18, 19, 38, 6025, 40, 49, 551, 8, 12, 14, 17...3, 20cytosolnucleoplasmp-5T-MDC1 K63PolyUb:K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-NucleosomeHIST3H3 HIST1H2BH ADPUBE2N XRCC5 XRCC6 p-5T-MDC1 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:RIF1:PAX1IP:DCLRE1Cp-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S645-DCLRE1C:DNA DSB endsBRCC3HIST1H2BK HDR throughHomologousRecombination (HR)or Single StrandAnnealing (SSA)p-T2609,S2612,T2638,T2647-PRKDC XRCC4 HIST3H3 HIST3H2BB HIST1H2BL p-S516,S645-DCLRE1C PIAS4 p-T2609,S2612,T2638,T2647-PRKDC UBE2N p-T2609,S2612,T2638,T2647-PRKDC KAT5 ATPPPip-S25,S1778-TP53BP1 DCLRE1CUIMC1 dsDNA with translocation p-S516,S645-DCLRE1C POLM UBE2N HIST1H2BN p-S406-FAM175A RNF168DNADNADSBs: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 complexMRE11A HIST2H2BE HIST1H2BB UBE2N RNF8 HIST1H2BB p-T2609,S2612,T2638,T2647-PRKDC KAT5HIST1H2BL HIST1H2BH HIST1H2BK Zn2+ MRE11A XRCC6 Extended ligatable DNA DSB ends HIST3H2BB p-S102-WHSC1HIST1H2BJ POLM UIMC1XRCC5 DNA double-strand break ends LIG4 HIST2H2BE Zn2+ p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:DNA DSB endsBRCC3 HIST1H2BB p-S102-WHSC1 p-S516,S645-DCLRE1C HIST1H2BL p-S25,S1778-TP53BP1 NHEJ1 HIST1H2BM K63PolyUb-K14,K16,p-S139-H2AFX p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:Ligatable DNA DSB endsHIST1H2BN XRCC6 RAD50 dsDNA HIST1H2BC PRKDCDNA double-strand break ends K63PolyUb-K14,K16,p-S139-H2AFX p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:DNA DSB endsXRCC5 dsDNA with microdeletion TDP1,TDP2HIST1H2BD Ligatable DNA DSB ends PAXIP1HIST1H2BO HERC2-SUMO1 p-S1981,Ac-K3016-ATM MRE11A p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:Trimmed DNA DSB endsRNF168 Ligatable DNA DSB ends dNTPHIST2H2BE p-T2609,S2612,T2638,T2647-PRKDC PAXIP1 p-S988,S1387,S1423,S1524,S1547-BRCA1 XRCC5:XRCC6p-5T-MDC1 p-S25,S1778-TP53BP1H2BFS K63PolyUb-K14,K16,p-S139-H2AFX HIST1H2BC HIST1H2BO Me2K21-HIST1H4 RIF1 K63PolyUb-K14,K16,p-S139-H2AFX HERC2-SUMO1 PRKDC:XRCC5:XRCC6:DNA DSB endsXRCC4 p-T2609,S2612,T2638,T2647-PRKDCRNF8 RAD50 POLL p-T2609,S2612,T2638,T2647-PRKDC HIST1H2BH PIAS4HERC2-SUMO1 RNF168 DCLRE1C PIAS4 XRCC6 ATPSUMO1:p-T4827-HERC2XRCC5:XRCC6:DNA DSBsp-S645-DCLRE1CH2BFS RNF8:Zn2+BABAM1HIST1H2BM PRKDC Trimmed DNA DSB ends p-T4827,SUMO1-HERC2 HIST1H2BM p-5S-BRCA1:p-2T-BARD1p-S102-WHSC1 TDP2 p-S406-FAM175AXRCC5 RAD50 XRCC6 p-T714,T734-BARD1 Zn2+ XRCC6 HIST1H2BK LIG4 RAD50 POLL,POLMXRCC6 UBE2V2 p-T4827,SUMO1-HERC2 HIST1H2BN HIST3H3 BABAM1 TDP1 p-T4827,SUMO1-HERC2 HIST1H2BA KAT5 HIST3H3 DNA double-strand break ends NHEJ1BRE HIST1H2BH MRE11A HIST1H2BC p-S1981,Ac-K3016-ATM HIST1H2BA HIST1H2BD p-S988,S1387,S1423,S1524,S1547-BRCA1 HIST3H2BB DNA double-strand break ends Me2K21-HIST1H4 UBE2V2 H2BFS p-S343-NBN RIF1p-S25,S1778-TP53BP1 HIST1H2BN p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:XRCC4:LIG4:NHEJ1:POLL,POLM:Ligatable DNA DSB endsRNF8 DNA double-strand break ends PAXIP1 RNF8 XRCC5 HIST1H2BD HIST1H2BC NHEJ1 HIST1H2BO DNA double-strand break ends Me2K21-HIST1H4 p-S1981,Ac-K3016-ATMXRCC4 DNA Double StrandBreak ResponseHIST1H2BM XRCC5 XRCC4:LIG4HIST1H2BJ XRCC5 NHEJ1 HIST1H2BA POLL PIAS4 HIST1H2BJ ADPUBE2N:UBE2V2Me2K21-HIST1H4 ds DNA, mutateddsDNAp-5T-MDC1ADPp-S1981,Ac-K3016-ATM DNA double-strand break ends HIST3H2BB p-S343-NBN HERC2-SUMO1 XRCC6 XRCC5 Zn2+ p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:XRCC4:LIG4:NHEJ1:POLL,POLM:Extended ligatable DNA DSB endsXRCC6 p-S343-NBN p-S516,S645-DCLRE1C RIF1 p-MRNBREHIST1H2BO ATPPOLL DNA double-strand break ends HIST1H2BJ LIG4 POLM p-T714,T734-BARD1 XRCC5 HIST1H2BA p-S516,S645-DCLRE1Cp-S343-NBN p-S102-WHSC1 p-T4827,SUMO1-HERC2 p-S516,S645-DCLRE1C p-S645-DCLRE1C 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:RIF1:PAXIP1XRCC5 UBE2V2 H2BFS XRCC6 RNF168 HIST2H2BE HIST1H2BK HIST1H2BL KAT5 HIST1H2BD UBE2V2 p-T2609,S2612,T2638,T2647-PRKDC p-5T-MDC1 HIST1H2BB 171515155115515715594336


Description

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). View original pathway at:Reactome.

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Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
123635view09:43, 7 August 2022EgonwModified title
114784view16:27, 25 January 2021ReactomeTeamReactome version 75
113229view11:29, 2 November 2020ReactomeTeamReactome version 74
112451view15:40, 9 October 2020ReactomeTeamReactome version 73
101358view11:24, 1 November 2018ReactomeTeamreactome version 66
100896view20:59, 31 October 2018ReactomeTeamreactome version 65
100437view19:34, 31 October 2018ReactomeTeamreactome version 64
99986view16:17, 31 October 2018ReactomeTeamreactome version 63
99540view14:52, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93783view13:36, 16 August 2017ReactomeTeamreactome version 61
93316view11:20, 9 August 2017ReactomeTeamreactome version 61
88066view14:29, 25 July 2016RyanmillerOntology Term : 'non-homologous end joining pathway of double-strand break repair' added !
88065view14:28, 25 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86401view09:17, 11 July 2016ReactomeTeamreactome version 56
83440view12:25, 18 November 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
BABAM1 ProteinQ9NWV8 (Uniprot-TrEMBL)
BABAM1ProteinQ9NWV8 (Uniprot-TrEMBL)
BRCC3 ProteinP46736 (Uniprot-TrEMBL)
BRCC3ProteinP46736 (Uniprot-TrEMBL)
BRE ProteinQ9NXR7 (Uniprot-TrEMBL)
BREProteinQ9NXR7 (Uniprot-TrEMBL)
DCLRE1C ProteinQ96SD1 (Uniprot-TrEMBL)
DCLRE1CProteinQ96SD1 (Uniprot-TrEMBL)
DNA

DNA

DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:RIF1:PAX1IP:DCLRE1C		ComplexR-HSA-5686907 (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:RIF1:PAXIP1		ComplexR-HSA-5686692 (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 Double Strand Break ResponsePathwayR-HSA-5693606 (Reactome) DNA double strand break (DSB) response involves sensing of DNA DSBs by the MRN complex which triggers ATM activation. ATM phosphorylates a number of proteins involved in DNA damage checkpoint signaling, as well as proteins directly involved in the repair of DNA DSBs. For a recent review, please refer to Ciccia and Elledge, 2010.
DNA double-strand break ends R-NUL-75165 (Reactome)
Extended ligatable DNA DSB ends R-NUL-5687361 (Reactome)
H2BFS ProteinP57053 (Uniprot-TrEMBL)
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).

HERC2-SUMO1 ProteinP63165 (Uniprot-TrEMBL)
HIST1H2BA ProteinQ96A08 (Uniprot-TrEMBL)
HIST1H2BB ProteinP33778 (Uniprot-TrEMBL)
HIST1H2BC ProteinP62807 (Uniprot-TrEMBL)
HIST1H2BD ProteinP58876 (Uniprot-TrEMBL)
HIST1H2BH ProteinQ93079 (Uniprot-TrEMBL)
HIST1H2BJ ProteinP06899 (Uniprot-TrEMBL)
HIST1H2BK ProteinO60814 (Uniprot-TrEMBL)
HIST1H2BL ProteinQ99880 (Uniprot-TrEMBL)
HIST1H2BM ProteinQ99879 (Uniprot-TrEMBL)
HIST1H2BN ProteinQ99877 (Uniprot-TrEMBL)
HIST1H2BO ProteinP23527 (Uniprot-TrEMBL)
HIST2H2BE ProteinQ16778 (Uniprot-TrEMBL)
HIST3H2BB ProteinQ8N257 (Uniprot-TrEMBL)
HIST3H3 ProteinQ16695 (Uniprot-TrEMBL)
K63PolyUb-K14,K16,p-S139-H2AFX ProteinP16104 (Uniprot-TrEMBL)
K63PolyUb:K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-NucleosomeComplexR-HSA-5682998 (Reactome)
KAT5 ProteinQ92993 (Uniprot-TrEMBL)
KAT5ProteinQ92993 (Uniprot-TrEMBL)
LIG4 ProteinP49917 (Uniprot-TrEMBL)
Ligatable DNA DSB ends R-NUL-75914 (Reactome)
MRE11A ProteinP49959 (Uniprot-TrEMBL)
Me2K21-HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
NHEJ1 ProteinQ9H9Q4 (Uniprot-TrEMBL)
NHEJ1ComplexR-HSA-5687234 (Reactome)
PAXIP1 ProteinQ6ZW49 (Uniprot-TrEMBL)
PAXIP1ProteinQ6ZW49 (Uniprot-TrEMBL)
PIAS4 ProteinQ8N2W9 (Uniprot-TrEMBL)
PIAS4ProteinQ8N2W9 (Uniprot-TrEMBL)
POLL ProteinQ9UGP5 (Uniprot-TrEMBL)
POLL,POLMComplexR-HSA-5687355 (Reactome)
POLM ProteinQ9NP87 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKDC ProteinP78527 (Uniprot-TrEMBL)
PRKDC:XRCC5:XRCC6:DNA DSB endsComplexR-HSA-75907 (Reactome)
PRKDCProteinP78527 (Uniprot-TrEMBL)
RAD50 ProteinQ92878 (Uniprot-TrEMBL)
RIF1 ProteinQ5UIP0 (Uniprot-TrEMBL)
RIF1ProteinQ5UIP0 (Uniprot-TrEMBL)
RNF168 ProteinQ8IYW5 (Uniprot-TrEMBL)
RNF168ProteinQ8IYW5 (Uniprot-TrEMBL)
RNF8 ProteinO76064 (Uniprot-TrEMBL)
RNF8:Zn2+ComplexR-HSA-5682540 (Reactome)
SUMO1:p-T4827-HERC2ComplexR-HSA-5682612 (Reactome)
TDP1 ProteinQ9NUW8 (Uniprot-TrEMBL)
TDP1,TDP2ComplexR-HSA-175597 (Reactome)
TDP2 ProteinO95551 (Uniprot-TrEMBL)
Trimmed DNA DSB ends R-NUL-5687341 (Reactome)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2N:UBE2V2ComplexR-HSA-5682542 (Reactome)
UBE2V2 ProteinQ15819 (Uniprot-TrEMBL)
UIMC1 ProteinQ96RL1 (Uniprot-TrEMBL)
UIMC1ProteinQ96RL1 (Uniprot-TrEMBL)
XRCC4 ProteinQ13426 (Uniprot-TrEMBL)
XRCC4:LIG4ComplexR-HSA-75912 (Reactome)
XRCC5 ProteinP13010 (Uniprot-TrEMBL)
XRCC5:XRCC6:DNA DSBsComplexR-HSA-75906 (Reactome)
XRCC5:XRCC6ComplexR-HSA-75905 (Reactome)
XRCC6 ProteinP12956 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
dNTPMetaboliteCHEBI:16516 (ChEBI)
ds DNA, mutated dsDNAComplexR-HSA-75927 (Reactome)
dsDNA R-HSA-5649637 (Reactome)
dsDNA with microdeletion R-HSA-5687453 (Reactome)
dsDNA with translocation R-HSA-5687452 (Reactome)
p-5S-BRCA1:p-2T-BARD1ComplexR-HSA-5683809 (Reactome)
p-5T-MDC1 ProteinQ14676 (Uniprot-TrEMBL)
p-5T-MDC1ComplexR-HSA-5682525 (Reactome)
p-MRNComplexR-HSA-5682166 (Reactome)
p-S102-WHSC1 ProteinO96028 (Uniprot-TrEMBL)
p-S102-WHSC1ProteinO96028 (Uniprot-TrEMBL)
p-S1981,Ac-K3016-ATM ProteinQ13315 (Uniprot-TrEMBL)
p-S1981,Ac-K3016-ATMProteinQ13315 (Uniprot-TrEMBL)
p-S25,S1778-TP53BP1 ProteinQ12888 (Uniprot-TrEMBL)
p-S25,S1778-TP53BP1ProteinQ12888 (Uniprot-TrEMBL)
p-S343-NBN ProteinO60934 (Uniprot-TrEMBL)
p-S406-FAM175A ProteinQ6UWZ7 (Uniprot-TrEMBL)
p-S406-FAM175AProteinQ6UWZ7 (Uniprot-TrEMBL)
p-S516,S645-DCLRE1C ProteinQ96SD1 (Uniprot-TrEMBL)
p-S516,S645-DCLRE1CProteinQ96SD1 (Uniprot-TrEMBL)
p-S645-DCLRE1C ProteinQ96SD1 (Uniprot-TrEMBL)
p-S645-DCLRE1CProteinQ96SD1 (Uniprot-TrEMBL)
p-S988,S1387,S1423,S1524,S1547-BRCA1 ProteinP38398 (Uniprot-TrEMBL)
p-T2609,S2612,T2638,T2647-PRKDC ProteinP78527 (Uniprot-TrEMBL)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:DNA DSB endsComplexR-HSA-5687154 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:DNA DSB endsComplexR-HSA-5687161 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:Ligatable DNA DSB endsComplexR-HSA-5687345 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:Trimmed DNA DSB endsComplexR-HSA-5693546 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:XRCC4:LIG4:NHEJ1:POLL,POLM:Extended ligatable DNA DSB endsComplexR-HSA-5687362 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:XRCC4:LIG4:NHEJ1:POLL,POLM:Ligatable DNA DSB endsComplexR-HSA-5693617 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S645-DCLRE1C:DNA DSB endsComplexR-HSA-5686925 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDCProteinP78527 (Uniprot-TrEMBL)
p-T4827,SUMO1-HERC2 ProteinO95714 (Uniprot-TrEMBL)
p-T714,T734-BARD1 ProteinQ99728 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-5686704 (Reactome)
ADPArrowR-HSA-5687183 (Reactome)
ADPArrowR-HSA-5693575 (Reactome)
ATPR-HSA-5686704 (Reactome)
ATPR-HSA-5687183 (Reactome)
ATPR-HSA-5693575 (Reactome)
BABAM1ArrowR-HSA-5686685 (Reactome)
BRCC3ArrowR-HSA-5686685 (Reactome)
BREArrowR-HSA-5686685 (Reactome)
DCLRE1CR-HSA-5686900 (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:RIF1:PAX1IP:DCLRE1C		ArrowR-HSA-5686900 (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:RIF1:PAX1IP:DCLRE1C		R-HSA-5686704 (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:RIF1:PAX1IP:DCLRE1C		mim-catalysisR-HSA-5686704 (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:RIF1:PAXIP1		ArrowR-HSA-5686685 (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:RIF1:PAXIP1		ArrowR-HSA-5686704 (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:RIF1:PAXIP1		R-HSA-5686900 (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:RIF1:PAXIP1		R-HSA-5693599 (Reactome)
DNA

DNA

DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-5S,2T-BRCA1-A complex		R-HSA-5686685 (Reactome)
K63PolyUb:K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-NucleosomeArrowR-HSA-5693599 (Reactome)
KAT5ArrowR-HSA-5693599 (Reactome)
NHEJ1ArrowR-HSA-5693604 (Reactome)
NHEJ1R-HSA-5693574 (Reactome)
PAXIP1ArrowR-HSA-5693599 (Reactome)
PAXIP1R-HSA-5686685 (Reactome)
PIAS4ArrowR-HSA-5693599 (Reactome)
POLL,POLMArrowR-HSA-5693604 (Reactome)
POLL,POLMR-HSA-5693574 (Reactome)
PPiArrowR-HSA-5687360 (Reactome)
PRKDC:XRCC5:XRCC6:DNA DSB endsArrowR-HSA-5693615 (Reactome)
PRKDC:XRCC5:XRCC6:DNA DSB endsR-HSA-5693575 (Reactome)
PRKDC:XRCC5:XRCC6:DNA DSB endsmim-catalysisR-HSA-5693575 (Reactome)
PRKDCR-HSA-5693615 (Reactome)
R-HSA-5686685 (Reactome) RIF1 binds TP53BP1 phosphorylated by ATM at DNA double strand breaks (DSBs). RIF1 binding interferes with the accumulation of BRCA1:BARD1 heterodimers and associated proteins at DNA DSBs. Therefore, TP53BP1-mediated recruitment of RIF1 prevents RBBP8 (CtIP) binding to BRCA1:BARD1 and the subsequent resection of DNA DSBs. The action of RIF1 and TP53BP1 promotes non-homologous end joining (NHEJ) of DNA DSBs during G1 phase of the cell cycle, when sister chromatids are not available for homologous recombination-mediated repair (Zimmermann et al. 2013, Escribano-Diaz et al. 2013).

Similar to RIF1, PAX1IP (PTIP) is also recruited to DNA DSBs through interaction with ATM-phosphorylated TP53BP1. Since RIF1 and PAX1IP interact with different phosphorylated sites on TP53BP1, they can simultaneously bind TP53BP1 and colocalize in the majority of TP53BP1 foci. PAX1IP contributes to inhibition of DNA DSB resection mediated by BRCA1-recruited RBBP8 (CtIP) (Callen et al. 2013).

R-HSA-5686704 (Reactome) Activated ATM phosphorylates DCLRE1C (ARTEMIS) at serine residue S645. S645 phosphorylation is necessary for the function of DCLRE1C in non-homologous end joining (NHEJ) (Riballo et al. 2004, Poinsignon et al. 2004, Chen et al. 2005).
R-HSA-5686900 (Reactome) TP53BP1 is required for the recruitment of DCLRE1C (ARTEMIS) to DNA double strand breaks (DSBs) and ATM-mediated phosphorylation of DCLRE1C (Riballo et al. 2004). DCRLE1C directly interacts with the TP53BP1-binding protein PAX1IP (PTIP) (Wang et al. 2014).
R-HSA-5686924 (Reactome) DCLRE1C (ARTEMIS) forms a stable complex with PRKDC (DNA-PKcs), even in the absence of DNA ends (Ma et al. 2002). Autophosphorylation of PRKDC as well as ATM-mediated phosphorylation of DCLRE1C are not prerequisites for the interaction of PRKDC and DCLRE1C (Ding et al.2003).
R-HSA-5687183 (Reactome) PRKDC (DNA-PKcs) phosphorylates DCLRE1C (ARTEMIS) at least on serine residue S516, and this phosphorylation is necessary for the activation of DCLRE1C endonucleolytic activity (Ma et al. 2002, Ma et al. 2005, Soubeyrand et al. 2006) as it relieves an autoinhibitory conformation of DCLRE1C (Niewolik et al. 2006).
R-HSA-5687360 (Reactome) DNA polymerases mu (POLM) and lambda (POLL) facilitate non-homologous end joining (NHEJ) of DNA double strand breaks (DSBs) by filling single strand (ss) gaps (usually 1- or 2- nucleotide gaps) present at DNA DSB ends positioned for ligation in the synaptic complex containing XRCC5:XRCC6 (Ku), PRKDC (DNA-PKcs), DCLRE1C (ARTEMIS), XRCC4:LIG4 and NHEJ1 (XLF) (Mahajan et al. 2002, Lee et al. 2004, Fan and Wu 2004, McElhinny et al. 2005, Davis et al. 2008).
R-HSA-5693533 (Reactome) DCLRE1C (ARTEMIS) possesses an intrinsic 5' to 3' exonuclease activity. Upon binding to PRKDC (DNA-PKcs) at DNA double strand breaks (DSBs) and undergoing PRKDC-mediated phosphorylation, DCLRE1C acquires endonucleolytic activity towards 5' and 3' overhangs at DNA double strand breaks, and it also acquires a hairpin opening activity (Ma et al. 2002, Ma et al. 2005). Autophosphorylation of PRKDC, although not required for the kinase activity of PRKDC, is needed for the activation of the endonucleolytic activity of DCLRE1C, probably by inducing a conformational change in PRKDC that provides DCLRE1C with access to DNA ends (Goodarzi et al. 2006, Niewolik et al. 2006, Jiang et al. 2015).
R-HSA-5693574 (Reactome) A complex consisting of XRCC4 homodimer and DNA ligase IV (LIG4) (Sibanda et al. 2001) is recruited to the synaptic complex consisting of PRKDC (DNA-PKcs), XRCC5, XRCC6, DCLRE1C (ARTEMIS) and ligatable DNA double strand break (DSB) ends (Critchlow and Jackson 1997, Leber et al. 1998, Malu et al. 2012). XRCC4 directly interacts with XRCC5:XRCC6 (McElhinny et al. 2000, Hsu et al. 2002), while LIG4 directly interacts with PRKDC (Hsu et al. 2002) and DCLRE1C (Malu et al. 2012). NHEJ1 (XLF) homodimer binds XRCC4 and is recruited to DNA DSBs together with XRCC4 and LIG4, where it acts as a facilitator of LIG4 activity (Ahnesorg et al. 2006, Buck et al. 2006, Tsai et al. 2007, Li et al. 2008). DNA polymerases mu (POLM) or lambda (POLL) are recruited to DNA DSBs through interaction with the Ku complex (XRCC5:XRCC6) and XRCC4 (Mahajan et al. 2002, Lee et al. 2004, Fan and Wu 2004).
R-HSA-5693575 (Reactome) Autophosphorylation of DNA-PKcs (PRKDC) is required for NHEJ in vivo, especially for endonucleolytic processing of DNA double strand break ends, which makes them suitable for ligation (Chan et al, 2002; Ding et al, 2003). In vivo, PRKDC autophosphorylates at threonine residues T2609, T2638 and T2647, and serine residue S2612 (Douglas et al. 2002).
R-HSA-5693578 (Reactome) Free radical-induced DNA double strand breaks (DSBs) frequently have unligatable 3'-phosphoglycolate termini, while topoisomerase II (TOP2) inhibition produces unligatable 5'-ends, with a 5'-phosphotyrosil bond between the DNA DSB 5'-end and TOP2 (reviewed by Povirk 2012). Tyrosyl-DNA phosphodiesterase TDP1 is able to remove 3'-phosphoglycolate and plays an important role in non-homologous end joining (NHEJ) (Inamdar et al. 2002, Zhou et al. 2005, Zhou et al. 2009, Heo et al. 2015). Tyrosil-DNA phosphodiesterase TDP2 removes 5'-phosphotyrosine and is also involved in NHEJ (Gomez-Herreros et al. 2013).
R-HSA-5693599 (Reactome) Ionizing radiation (IR) induces single-strand breaks, i.e., cleavage of the phosphodiester backbone. When two single-strand breaks occur within approximately 10 base pairs, a DNA double-strand break (DSB) results. IR-induced DSBs are complex DNA damage lesions, frequently containing base damage, 5'-OH groups, and 3'-hydroxy or phosphoglycolate groups that must be removed prior to ligation in the final step of NHEJ (Friedberg et al, 1995; Nikjoo et al, 2001; Valerie and Povirk, 2003). The Ku70/80 heterodimer (XRCC5:XRCC6) (Walker et al., 2001) binds to the ends of the double-strand break. Ku can translocate inwards from the site of the break in an ATP-independent manner (reviewed in Dynan and Yoo, 1998). Binding of XRCC5:XRCC6 to DNA DSBs competes away the MRN complex and associated proteins from the DNA DSB (Sun et al. 2012).
R-HSA-5693604 (Reactome) The DNA ligase complex composed of DNA ligase 4 (LIG4) and the XRCC4 homodimer (Sibanda et al. 2000) catalyzes ligation of DNA double strand break (DSB) ends during non-homologous end joining (NHEJ). The XRCC4:LIG4 complex is recruited to NHEJ sites through interaction of its subunits with XRCC5:XRCC6 (Ku complex), PRKDC (DNA-PKcs) and DCLRE1C (ARTEMIS) (McElhinny et al. 2000, Hsu et al. 2002, Malu et al. 2012). Phosphorylation of XRCC4 by PRKDC may regulate the activity of the ligase complex (Lee et al. 2004). XRCC4:LIG4 can ligate incompatible DNA DSB ends, and may also ligate across single nucleotide gaps (Gu et al. 2007). The presence of the accessory protein NHEJ1 (XLF) facilitates XRCC4:LIG4 ligase activity, especially at mismatched DNA DSB ends (Ahnesorg et al. 2006, Buck et al. 2006, 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 Povirk 2012).
R-HSA-5693615 (Reactome) DNA-PKcs (PRKDC) is recruited to the Ku70:Ku80:DNA double strand break ends complex (XRCC5:XRCC6:DNA DSBs) (Gottlieb and Jackson, 1993), causing Ku to translocate inwards (away from the break) approximately 10 bp (Yoo and Dynan, 1999). This forms the DNA-PK complex (DNA-PKcs plus Ku70/Ku80) at each end of the DSB. Two DNA-PK complexes, one on either side of the DSB, interact to bring the DNA ends together.
RIF1ArrowR-HSA-5693599 (Reactome)
RIF1R-HSA-5686685 (Reactome)
RNF168ArrowR-HSA-5693599 (Reactome)
RNF8:Zn2+ArrowR-HSA-5693599 (Reactome)
SUMO1:p-T4827-HERC2ArrowR-HSA-5693599 (Reactome)
TDP1,TDP2mim-catalysisR-HSA-5693578 (Reactome)
UBE2N:UBE2V2ArrowR-HSA-5693599 (Reactome)
UIMC1ArrowR-HSA-5686685 (Reactome)
XRCC4:LIG4ArrowR-HSA-5693604 (Reactome)
XRCC4:LIG4R-HSA-5693574 (Reactome)
XRCC5:XRCC6:DNA DSBsArrowR-HSA-5693599 (Reactome)
XRCC5:XRCC6:DNA DSBsR-HSA-5693615 (Reactome)
XRCC5:XRCC6ArrowR-HSA-5693604 (Reactome)
XRCC5:XRCC6R-HSA-5693599 (Reactome)
dNTPR-HSA-5687360 (Reactome)
ds DNA, mutated dsDNAArrowR-HSA-5693604 (Reactome)
p-5S-BRCA1:p-2T-BARD1ArrowR-HSA-5686685 (Reactome)
p-5T-MDC1ArrowR-HSA-5693599 (Reactome)
p-MRNArrowR-HSA-5693599 (Reactome)
p-S102-WHSC1ArrowR-HSA-5693599 (Reactome)
p-S1981,Ac-K3016-ATMArrowR-HSA-5693599 (Reactome)
p-S25,S1778-TP53BP1ArrowR-HSA-5693599 (Reactome)
p-S406-FAM175AArrowR-HSA-5686685 (Reactome)
p-S516,S645-DCLRE1CArrowR-HSA-5693604 (Reactome)
p-S645-DCLRE1CArrowR-HSA-5686704 (Reactome)
p-S645-DCLRE1CR-HSA-5686924 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:DNA DSB endsArrowR-HSA-5693575 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:DNA DSB endsR-HSA-5686924 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:DNA DSB endsArrowR-HSA-5687183 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:DNA DSB endsR-HSA-5693533 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:DNA DSB endsmim-catalysisR-HSA-5693533 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:Ligatable DNA DSB endsArrowR-HSA-5693578 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:Ligatable DNA DSB endsR-HSA-5693574 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:Trimmed DNA DSB endsArrowR-HSA-5693533 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:Trimmed DNA DSB endsR-HSA-5693578 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:XRCC4:LIG4:NHEJ1:POLL,POLM:Extended ligatable DNA DSB endsArrowR-HSA-5687360 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:XRCC4:LIG4:NHEJ1:POLL,POLM:Extended ligatable DNA DSB endsR-HSA-5693604 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:XRCC4:LIG4:NHEJ1:POLL,POLM:Extended ligatable DNA DSB endsmim-catalysisR-HSA-5693604 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:XRCC4:LIG4:NHEJ1:POLL,POLM:Ligatable DNA DSB endsArrowR-HSA-5693574 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:XRCC4:LIG4:NHEJ1:POLL,POLM:Ligatable DNA DSB endsR-HSA-5687360 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S516,S645-DCLRE1C:XRCC4:LIG4:NHEJ1:POLL,POLM:Ligatable DNA DSB endsmim-catalysisR-HSA-5687360 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S645-DCLRE1C:DNA DSB endsArrowR-HSA-5686924 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S645-DCLRE1C:DNA DSB endsR-HSA-5687183 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDC:XRCC5:XRCC6:p-S645-DCLRE1C:DNA DSB endsmim-catalysisR-HSA-5687183 (Reactome)
p-T2609,S2612,T2638,T2647-PRKDCArrowR-HSA-5693604 (Reactome)
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