Fig. 4.

Synthetic lethality in tumors from BRCA1/2 mutation carriers treated with PARPi. PARPi induce PARP trapping and BER inhibition on sites with SSBs. SSBs in the cells are recognized by PARP1, that recruits downstream BER components to repair the damage. If the BER pathway is inhibited by PARPi in cells with heterozygous mutations in BRCA1/2 (BRCA1/2^+/−), PARP1 becomes trapped on the DNA. This causes the stalling and collapse of replication forks and the formation of DSBs, that should be repaired by HRR using the functional BRCA1/2 copy. The same happens in BRCA1/2^+/− cancer cells, resulting in cancer cell survival and drug resistance. However, these cancer cells often lose the wild-type copy of BRCA1/2 by loss of heterozygosity (LOH) and, in this case, when exposed to PARPi they can no longer repair the DSBs, leading to cancer cell death by SL between PARP1 (BER) and BRCA1/2 (HRR). Figure created with BioRender