FIGURE 4. A model for the selective effects of PARP inhibition on cells lacking wild-type BRCA1 and BRCA2.

a, PARP functions in base excision repair. DNA SSBs form due to oxidative damage and its repair. Inhibition of PARP activity prevents the recruitment of XRCC1 and subsequent SSB gap filling by DNA polymerases. Large numbers of DNA SSBs persist and are encountered by DNA replication forks. These lead to replication fork arrest associated with a DSB. b, In the presence of functional BRCA1 and BRCA2, the proximity of an undamaged sister chromatid template to the DSB allows the invasion of the sister chromatid by a RAD51-coated single-stranded DNA filament, and initiation of sister chromatid recombination repair. This is associated with the formation of nuclear RAD51 foci. A collapsed replication fork may be restarted by this mechanism. c, When Holliday junctions at recombination intermediates are resolved, a sister chromatid exchange may occur. The excess number of replication fork arrests associated with loss of PARP function leads to an increase in sister chromatid recombination events and sister chromatid exchanges. d, In the absence of functional BRCA1 or BRCA2, sister chromatid recombination and the formation of RAD51 foci are severely impaired. Replication-associated DSBs cannot be repaired by sister chromatid recombination. Some remain unrepaired as chromatid breaks but many are repaired by error-prone RAD51-independent mechanisms such as non-homologous end joining (NHEJ) and single-strand annealing (SSA). These cause complex chromatid rearrangements. These cells arrest at the G2/M checkpoint and permanently arrest or undergo apoptosis.