FANCM 调节复制叉停滞时的修复途径选择。
FANCM regulates repair pathway choice at stalled replication forks.
机构信息
Department of Medicine, Division of Hematology-Oncology and Cancer Research Institute, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA 02215, USA.
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA.
出版信息
Mol Cell. 2021 Jun 3;81(11):2428-2444.e6. doi: 10.1016/j.molcel.2021.03.044. Epub 2021 Apr 20.
Repair pathway "choice" at stalled mammalian replication forks is an important determinant of genome stability; however, the underlying mechanisms are poorly understood. FANCM encodes a multi-domain scaffolding and motor protein that interacts with several distinct repair protein complexes at stalled forks. Here, we use defined mutations engineered within endogenous Fancm in mouse embryonic stem cells to study how Fancm regulates stalled fork repair. We find that distinct FANCM repair functions are enacted by molecularly separable scaffolding domains. These findings define FANCM as a key mediator of repair pathway choice at stalled replication forks and reveal its molecular mechanism. Notably, mutations that inactivate FANCM ATPase function disable all its repair functions and "trap" FANCM at stalled forks. We find that Brca1 hypomorphic mutants are synthetic lethal with Fancm null or Fancm ATPase-defective mutants. The ATPase function of FANCM may therefore represent a promising "druggable" target for therapy of BRCA1-linked cancer.
在停滞的哺乳动物复制叉处，修复途径“选择”是基因组稳定性的重要决定因素；然而，其潜在机制尚未被充分理解。FANCM 编码一种多结构域支架和运动蛋白，它与停滞叉处的几个不同的修复蛋白复合物相互作用。在这里，我们使用在小鼠胚胎干细胞内设计的内源性 Fancm 中的明确突变来研究 Fancm 如何调节停滞叉修复。我们发现，不同的 FANCM 修复功能是由分子上可分离的支架结构域执行的。这些发现将 FANCM 定义为停滞复制叉处修复途径选择的关键介质，并揭示了其分子机制。值得注意的是，失活 FANCM ATP 酶功能的突变会使 FANCM 的所有修复功能失活，并使 FANCM“困”在停滞的叉上。我们发现 Brca1 功能不全突变体与 Fancm 缺失或 Fancm ATP 酶缺陷突变体是合成致死的。因此，FANCM 的 ATP 酶功能可能代表了治疗 BRCA1 相关癌症的有前途的“可用药”靶标。
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