PARP inhibitor (PARPi) is widely used to treat BRCA1/2-deficient tumors, but why PARPi is more effective than other DNA-damaging drugs is unclear. Here, we show that PARPi generates DNA double-strand breaks (DSBs) predominantly in a trans cell cycle manner. During the first S phase after PARPi exposure, PARPi induces single-stranded DNA (ssDNA) gaps behind DNA replication forks. By trapping PARP on DNA, PARPi prevents the completion of gap repair until the next S phase, leading to collisions of replication forks with ssDNA gaps and a surge of DSBs. In the second S phase, BRCA1/2-deficient cells are unable to suppress origin firing through ATR, resulting in continuous DNA synthesis and more DSBs. Furthermore, BRCA1/2-deficient cells cannot recruit RAD51 to repair collapsed forks. Thus, PARPi induces DSBs progressively through trans cell cycle ssDNA gaps, and BRCA1/2-deficient cells fail to slow down and repair DSBs over multiple cell cycles, explaining the unique efficacy of PARPi in BRCA1/2-deficient cells.

中文翻译：

---

PARP 抑制剂的跨细胞周期效应是它们对 BRCA1/2 缺陷细胞选择性的基础

PARP 抑制剂 (PARPi) 广泛用于治疗 BRCA1/2 缺陷型肿瘤，但为什么 PARPi 比其他 DNA 损伤药物更有效尚不清楚。在这里，我们表明 PARPi 主要以反式产生 DNA 双链断裂 (DSB)细胞周期方式。在 PARPi 暴露后的第一个 S 期，PARPi 在 DNA 复制叉后面诱导单链 DNA (ssDNA) 间隙。通过将 PARP 捕获在 DNA 上，PARPi 阻止了间隙修复的完成，直到下一个 S 期，导致复制叉与 ssDNA 间隙的碰撞和 DSB 的激增。在第二个 S 期，BRCA1/2 缺陷细胞无法通过 ATR 抑制起源放电，导致持续的 DNA 合成和更多的 DSB。此外，BRCA1/2 缺陷细胞不能募集 RAD51 来修复塌陷的叉。因此，PARPi 通过跨细胞周期 ssDNA 间隙逐步诱导 DSB，而 BRCA1/2 缺陷细胞在多个细胞周期内无法减缓和修复 DSB，这解释了 PARPi 在 BRCA1/2 缺陷细胞中的独特功效。