Figure 1

Example of synthetic lethality: PARP inhibition in cells deficient in homologous recombination (HR). (a) In normal cells, repair pathways, including base excision repair (BER) and HR, are intact. Single-strand breaks (SSBs) are readily repaired by BER, with the participation of PARP1, and double-strand breaks (DSBs) are reliably repaired by HR, with the participation of BRCA1 and BRCA2. (b) Cells with mutations in BRCA1 or BRCA2 are deficient in HR. Other repair pathways, including the BER pathway, are able to minimize the number of lesions that become DSBs. (c) Normal cells treated with PARP inhibitors may become deficient in BER. Therefore, more SSBs go unrepaired. During replication, the replication fork may stall, resulting in the conversion of SSBs into DSBs. HR can repair these DSBs in an error-free manner. (d) When PARP inhibitors are delivered to cells deficient in HR (for example, BRCA-mutated cells), synthetic lethality can result. Inhibition of BER by PARP inhibitors results in the conversion of unrepaired SSBs into DSBs. These DSBs cannot be repaired by HR in an error-free manner and can therefore result in cell death. PARP, poly(ADP-ribose) polymerase.