| 53BP1, or tumor protein p53-binding protein 1, functions as a central mediator in the DNA damage response, originally identified as a p53 transcriptional coactivator and now recognized for orchestrating double-strand break (DSB) repair pathway choice. It features an N-terminal region with multiple ATM/ATR-phosphorylated S/TQ sites, a central oligomerization domain flanked by a GAR motif and LC8-binding site, tandem Tudor domains binding dimethylated histone H4K20, a ubiquitin-dependent recruitment (UDR) motif engaging H2AK15ub, and C-terminal BRCT repeats. Recruitment to DSBs occurs via H4K20me2 and H2AK15ub recognition following RNF8/RNF168 ubiquitination downstream of γH2AX-MDC1, with oligomerization amplifying chromatin binding and ST/Q phosphorylation recruiting effectors Rif1 and PTIP. 53BP1 promotes classical non-homologous end-joining (c-NHEJ) by recruiting Rif1 to block CtIP-dependent 5′ resection, favoring ligation over homology-directed repair (HDR), while PTIP aids NHEJ in BRCA1-deficient contexts; it enhances heterochromatic repair via BRCT-KAP1/EXPAND1 interactions and stimulates DSB mobility/synapsis for efficient joining in CSR and telomere fusion. ATM phosphorylates multiple sites including Ser25/29/166/Ser25, but these prove dispensable for focus formation yet essential for effector binding. 53BP1 ensures G2/M and intra-S checkpoints via p53/Chk2/Brca1 phosphorylation, supports immunoglobulin class switch recombination and V(D)J joining, and maintains telomere stability. Loss impairs G2/M arrest post-IR, reduces Brca1 foci, and shifts repair toward HDR, sensitizing to PARP inhibitors in BRCA1-null settings while promoting synthetic lethality reversal. |
