FANCM regulates repair pathway choice at stalled replication forks.

Document Type

Article

Publication Date

6-3-2021

Publication Title

Molecular cell

Keywords

JGM

JAX Source

Mol Cell 2021 Jun 3; 81(11):2428-2444.e6

Volume

81

Issue

11

First Page

2428

Last Page

2444

ISSN

1097-4164

PMID

33882298

DOI

https://doi.org/10.1016/j.molcel.2021.03.044

Grant

BC160172, CA034196

Abstract

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.

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