Synthetic Lethality in BRCA1/2 Defective Tumors. Naturally occurring single-strand breaks (SSBs) are primarily repaired by a PARP1-dependent pathway before a replication fork hits. However, if they are not repaired before the replication fork hits, the SSB is converted into a DSB. The DSB at the fork is usually repaired by a type of DSB repair termed homologous recombination (HR), which requires BRCA1/2, denoted in red. Thus, BRCA1/2 are needed to restart the collapsed replication forks caused by the DSB. In BRCA1 or 2 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 2 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. Normal tissue, which does not have the bi-allelic defects in BRCA1 or 2, would not be affected.Reprinted from Blood. See reference number 4.