Synthetic lethality. (A) DNA lesions are often processed by multiple pathways that promote survival. Lesions can be lethal if all routes to repair are blocked. This is the basis for synthetic lethality. (B) Synthetic lethality in BRCA1/2-defective tumors. Naturally occurring single-strand breaks (SSBs) are primarily repaired by PARP1-dependent pathway before a replication fork hits. However, if they are not repaired in time before the replication fork hits, the SSB turns into a DSB. The DSB at the fork is repaired by HR, which requires BRCA1 and 2, denoted in red. Thus, BRCA1 and 2 are needed to restart the collapsed replication forks caused by the DSB. In BRCA1- or BRCA2-defective tumors, these SSBs must be repaired by the PARP1 pathway before the replication fork hits, as there is no mechanism of repairing the resultant DSB. Thus, PARP inhibitors result in synthetic lethality of the BRCA1- or BRCA2-defective cancer cell, because the SSB cannot be repaired in front of the replication fork, and the resultant DSB caused by the progression of the fork through the SSB also cannot be repaired. Note that normal tissue, which does not have the bi-allelic defects in BRCA1 or 2, would not be affected.