Abstract：
Poly(ADP-ribose) polymerase inhibitors (PARPis) exhibit remarkable anticancer activity in tumors with homologous recombination (HR) gene mutations. However, the role of other DNA repair proteins in PARPi-induced lethality remains elusive. Here, we reveal that FANCM promotes PARPi resistance independent of the core Fanconi anemia (FA) complex. FANCM-depleted cells retain HR proficiency, acting independently of BRCA1 in response to PARPis. FANCM depletion leads to increased DNA damage in the second S phase after PARPi exposure, driven by elevated single-strand DNA (ssDNA) gap formation behind replication forks in the first S phase. These gaps arise from both 53BP1- and primase and DNA directed polymerase (PRIMPOL)-dependent mechanisms. Notably, FANCM-depleted cells also exhibit reduced resection of collapsed forks, while 53BP1 deletion restores resection and mitigates PARPi sensitivity. Our results suggest that FANCM counteracts 53BP1 to repair PARPi-induced DNA damage. Furthermore, FANCM depletion leads to increased chromatin bridges and micronuclei formation after PARPi treatment, elucidating the mechanism underlying extensive cell death in FANCM-depleted cells.
摘要：
聚(ADP-核糖)聚合酶抑制剂(PARPis)在具有同源重组(HR)基因突变的肿瘤中表现出显著的抗癌活性。然而,其他DNA修复蛋白在PARPi诱导的致死率中的作用仍然难以捉摸。这里,我们揭示了FANCM促进PARPi抵抗，而与核心Fanconi贫血（FA）复合物无关。FANCM耗尽细胞保留HR能力，对PARPis的反应独立于BRCA1。FANCM耗竭导致PARPi暴露后第二个S期DNA损伤增加，由第一S期复制叉后的单链DNA（ssDNA）间隙形成驱动。这些缺口来自53BP1-和引发酶以及DNA定向聚合酶（PRIMPOL）依赖性机制。值得注意的是,FANCM耗尽的细胞也表现出塌陷叉的切除减少，而53BP1缺失恢复切除并降低PARPi敏感性。我们的结果表明，FANCM可以抵消53BP1以修复PARPi诱导的DNA损伤。此外，FANCM耗竭导致PARPi治疗后染色质桥和微核形成增加，阐明FANCM耗竭细胞中广泛细胞死亡的潜在机制。
