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着的抗癌活性。然而，其他 DNA 修复蛋白在 PARPi 诱导的致死中的作用仍然难以捉摸。在这里，我们揭示了 FANCM 促进 PARPi 抵抗，独立于核心范可尼贫血 (FA) 复合体。 FANCM 耗尽的细胞保留 HR 能力，独立于 BRCA1 响应 PARPis。 FANCM 耗竭导致 PARPi 暴露后第二个 S 期的 DNA 损伤增加，这是由第一个 S 期复制叉后面单链 DNA (ssDNA) 间隙形成增加所驱动。这些缺口是由 53BP1 和引物酶以及 DNA 定向聚合酶 (PRIMPOL) 依赖性机制引起的。值得注意的是，FANCM 耗尽的细胞还表现出塌陷叉的切除减少，而 53BP1 缺失则恢复切除并减轻 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 耗尽导致 PARPi 处理后染色质桥和微核形成增加，阐明了 FANCM 耗尽细胞中广泛细胞死亡的机制。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.