Fig. 2
From: PARP inhibitor resistance: the underlying mechanisms and clinical implications
Homologous recombination repair in S/G2 phase. The double-strand break ends are resected by MRE11-RAD50-NBS1(MRN) complex together with CtIP. ATM is recruited to DSBs through MRN and phosphorylates targets such as 53BP1 and MDC1. MDC1 phosphorylation recruits the E3 ubiquitin ligase RNF8, which, through recruitment of a second E3 ubiquitin ligase (RNF168), leads to histone H2A ubiquitylation. This modification, together with H4K20 methylation, allows for 53BP1 recruitment. 53BP1 phosphorylation allows its interaction with RIF1 and PTIP, which can be blocked by WIP1. 53BP1 blocks DNA resection by recruiting shieldin and presents cells to NHEJ. While, BRCA1 counteracts the protection function of 53BP1, leading to the resection of DNA ends. Afterwards, the resected DNA ends are coated by PRA. With the favor of PALB2, BRCA2 binds with BRCA1 and promotes the loading of RAD51. The RAD51 mediates the invasion of the homologous sequence and formation of the nucleoprotein filament and D-loop by eliminating secondary structure formation. EMI and DDB2 mediate the degradation of RAD51. TOPBP1 phosphorylates RAD51. BRD4 and HORMAD1 are key regulators of RAD51 accumulation on chromatin. P, phosphorylation; Ub, ubiquitylation; Me, methylation, SUMO, SUMOylation, red arrows, resection