Figure 3.

Synthetic and contextual lethality: Endogenous and exogenous stress induce both SSBs/DSBs. Inhibitors of PARP prevent repair of SSBs, which are further processed to DSBs if encountered at a replication fork. Tumours with HR mutations such as BRCA2 (synthetic lethal), or cancer cells which have disseminated away from the nearest blood vessel and exhibit hypoxic suppression of HR proteins (contextual lethal) are unable to efficiently repair DSBs using HR. This leads to DSB accumulation, mitotic catastrophe and selective tumour cell killing. DSB, double stranded breaks; HR, homologous recombination; PARP, poly ADP ribose polymerase; SSB, single stranded breaks