Figure 3.

PARP1 at intersecting repair pathways. PARP1 promotes base excision repair (BER) and cell survival. PARP1 inhibitors (PARP1i) cause unrepaired intermediates such as SS nicks to accumulate. They also trap PARP1 on chromatin, causing replication forks to stall. Double-strand breaks are either from the collision of the fork with a BER SS nick repair intermediate or from nuclease cleavage of a stalled replication fork. Collapsed replication forks are repaired and restarted by homologous recombination (HR) promoted by PARP1 modification of MRE11, which initiates 5’ end resection. In HR-deficient cells (eg, BRCA1/2 mutants), HR repair of stalled forks cannot occur, accounting for the synthetic lethality of PARP1i in HR-deficient cancers. BER = base excision repair; DSB = double-strand break; HR = homologous recombination; SSB = single-strand break.