Base excision repair, PARP & alkylation damage

Damaged bases (8-oxoguanine, uracil, alkylated bases from temozolomide or endogenous methylation) are removed by glycosylases (OGG1, UNG, MPG), APE1 cuts the backbone, PARP1 binds the single-strand break and PARylates itself and histones to recruit XRCC1, Pol β fills the gap and LIG3 seals it (short-patch) or FEN1/LIG1 (long-patch). PARP inhibitors compete with NAD+ and, crucially, trap PARP1 on DNA (talazoparib >> olaparib > veliparib in trapping potency), so replication forks collide with the complex and collapse into double-strand breaks that only HR can fix, the mechanistic basis of BRCA synthetic lethality; PARP1-selective saruparib spares PARP2 and bone marrow. O6-methylguanine, the lethal TMZ lesion, is reversed directly by MGMT; MGMT promoter methylation predicts TMZ benefit in glioblastoma, and MMR is needed for TMZ toxicity. PARP inhibition also traps PARP at oxidative lesions from radiation and generates cytosolic DNA that fires cGAS-STING.