Pathway
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
Activated ATM phosphorylates a number of proteins involved in the DNA damage checkpoint and DNA repair, thereby triggering and coordinating accumulation of DNA DSB repair proteins in nuclear foci known as ionizing radiation-induced foci (IRIF). While IRIFs include chromatin regions kilobases away from the actual DSB site, this Reactome pathway represents simplified foci and events that happen proximal to the DNA DSB ends. In general, proteins localizing to the nuclear foci in response to ATM signaling are cooperatively retained at the DNA DSB site, forming a positive feedback loop and amplifying DNA damage response.
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Activated ATM phosphorylates the NBN (NBS1) subunit of the MRN complex (MRE11A:RAD50:NBN), as well as the nucleosome histone H2AFX (H2AX) on serine residue S139, producing gamma-H2AFX (gamma-H2AX) containing nucleosomes. H2AFX is phosphorylated on tyrosine 142 (Y142) under basal conditions. After ATM-mediated phosphorylation of H2AFX on S139, tyrosine Y142 has to be dephosphorylated by EYA family phosphatases in order for the DNA repair to proceed and to avoid apoptosis induced by DNA DSBs. Gamma-H2AFX recruits MDC1 to DNA DSBs. After ATM phosphorylates MDC1, the MRN complex, gamma-H2AFX nucleosomes, and MDC1 serve as a core of the nuclear focus and a platform for the recruitment of other proteins involved in DNA damage signaling and repair.
RNF8 ubiquitin ligase binds phosphorylated MDC1 and, in cooperation with HERC2 and RNF168, ubiquitinates H2AFX and histone demethylases KDM4A and KDM4B.
Ubiquitinated gamma-H2AFX recruits UIMC1 (RAP80), promoting the assembly of the BRCA1-A complex at DNA DSBs. The BRCA1-A complex consists of RAP80, FAM175A (Abraxas), BRCA1:BARD1 heterodimer, BRCC3 (BRCC36), BRE (BRCC45) and BABAM1 (MERIT40, NBA1)
Ubiquitin mediated degradation of KDM4A and KDM4B allows TP53BP1 (53BP1) to associate with histone H4 dimethylated on lysine K21 (H4K20Me2 mark) by WHSC1 at DNA DSB sites.
Once recruited to DNA DSBs, both BRCA1:BARD1 heterodimers and TP53BP1 are phosphorylated by ATM, which triggers recruitment and activation of CHEK2 (Chk2, Cds1).
Depending on the cell cycle stage, BRCA1 and TP53BP1 competitively promote either homology directed repair (HDR) or nonhomologous end joining (NHEJ) of DNA DSBs. HDR through homologous recombination repair (HRR) or single strand annealing (SSA) is promoted by BRCA1 in association with RBBP8 (CtIP), while NHEJ is promoted by TP53BP1 in association with RIF1.
What the reference databases state
Statements
59 statements
59 statements · 1 reference database · Subject: Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks · Sources: Reactome
- ABL1 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- ABRAXAS1 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- APBB1 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- ATM participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- BABAM1 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- BABAM2 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- BAP1 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- BARD1 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- BAZ1B participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- BRCA1 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- BRCC3 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- CHEK2 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
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- EYA1 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- EYA2 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- EYA3 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- EYA4 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- H2AX participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- H2BC1 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- H2BC11 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- H2BC12 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- H2BC13 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- H2BC14 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- H2BC15 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- H2BC17 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- H2BC21 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- H2BC26 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- H2BC3 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- H2BC4; H2BC6; H2BC7; H2BC8; H2BC10 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- H2BC9 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- H3-4 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- H4C1; H4C2; H4C3; H4C4; H4C5; H4C6; H4C8; H4C9; H4C11; H4C12; H4C13; H4C14; H4C15; H4C16 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- HERC2 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- KAT5 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- KDM4A participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- KDM4B participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- MAPK8 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- MDC1 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- MRE11 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- NBN participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- NSD2 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- PHF6 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- PIAS4 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- PPP5C participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- RAD50 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- RNF168 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- RNF8 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- RPS27A participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- SMARCA5 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- SUMO1 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- TP53 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- TP53BP1 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- UBA52 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- UBB participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- UBC participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- UBE2I participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- UBE2N participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- UBE2V2 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- UBXN1 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only
- UIMC1 participates in Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksProteinReactome R-HSA-5693565Inferred only