Fanconi anemia proteins participate in a break-induced-replication-like pathway to counter replication stress
Xu Xinlin, Xu Yixi, Guo Ruiyuan, Xu Ran, Fu Congcong, Xing Mengtan, Sasanuma Hiroyuki, Li Qing, Takata Minoru, Takeda Shunichi, Guo Rong, Xu Dongyi
Journal：NATURE STRUCTURAL & MOLECULAR BIOLOGY
IF：15.37
DOI：10.1038/s41594-021-00602-9
PMID：34117478
Published：2021-06-10
research field：神经科学分子生物学药理学细胞生物学
Abstract
Fanconi anemia (FA) is a devastating hereditary disease characterized by bone marrow failure (BMF) and acute myeloid leukemia (AML). As FA-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), ICLs are widely assumed to be the lesions responsible for FA symptoms. Here, we show that FA-mutated cells are hypersensitive to persistent replication stress and that FA proteins play a role in the break-induced-replication (BIR)-like pathway for fork restart. Both the BIR-like pathway and ICL repair share almost identical molecular mechanisms of 53BP1–BRCA1-controlled signaling response, SLX4- and FAN1-mediated fork cleavage and POLD3-dependent DNA synthesis, suggesting that the FA pathway is intrinsically one of the BIR-like pathways. Replication stress not only triggers BMF in FA-deficient mice, but also specifically induces monosomy 7, which is associated with progression to AML in patients with FA, in FA-deficient cells.
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