Figure 7.

Models for the trans cell cycle effects of PARPi in BRCA1-proficient and -deficient cells. (A) A model for the effects of PARPi in BRCA1/2-proficient and -deficient cells during two consecutive S phases. During each S phase, PARPi induces ssDNA gaps behind DNA replication forks. The trapping of PARP by PARPi prevents complete filling of these gaps, allowing them to persist into the next cell cycle. During the next round of DNA replication, the ssDNA gaps generated in the previous cell cycle collide with replication forks, leading to fork collapse and a surge of DSBs. BRCA1/2-proficient cells activate ATR to suppress replication origin firing and recruit RAD51 to repair collapsed forks. In contrast, BRCA1/2-deficient cells fail to suppress origin firing and repair collapsed forks, leading to more DSBs. The unique ability of PARPi to induce DSBs in a trans cell cycle manner explains why PARPi generates more DSBs in BRCA1/2-deficeint cells than in BRCA1/2-proficient cells. (B) A model for the effects of PARPi in BRCA1/2-proficient and -deficient cells over multiple cell cycles. The ssDNA gaps generated in each S phase are converted to DSBs in the next S phase. Because BRCA1/2-proficient cells slow down and repair DSBs in each cell cycle, DSB levels will not reach the threshold for cell death, and cells will continue to proliferate after DSBs are repaired. In contrast, BRCA1/2-deficient cells fail to slow down and repair in each cell cycle, which allows PARPi-induced DSBs to accumulate progressively over multiple cell cycles. These repeating trans cell cycle effects of PARPi eventually push DSB levels over the lethal threshold and kill BRCA1/2-deficient cancer cells.