基因组不稳定性
DNA修复
染色质
DNA损伤
DNA复制
DNA
生物
核酸外切酶
基因
细胞生物学
遗传学
分子生物学
DNA聚合酶
作者
Yuandi Gao,Laure Guitton-Sert,Julien Dessapt,Yan Coulombe,Amélie Rodrigue,Larissa Milano,Andréanne Blondeau,Nicolai Balle Larsen,Julien P. Duxin,Samer Hussein,Amélie Fradet-Turcotte,Jean-Yves Masson
标识
DOI:10.1038/s41467-023-35802-y
摘要
Fanconi Anemia (FA) is a rare, genome instability-associated disease characterized by a deficiency in repairing DNA crosslinks, which are known to perturb several cellular processes, including DNA transcription, replication, and repair. Formaldehyde, a by-product of metabolism, is thought to drive FA by generating DNA interstrand crosslinks (ICLs) and DNA-protein crosslinks (DPCs). However, the impact of formaldehyde on global cellular pathways has not been investigated thoroughly. Herein, using a pangenomic CRISPR-Cas9 screen, we identify EXO1 as a critical regulator of formaldehyde-induced DNA lesions. We show that EXO1 knockout cell lines exhibit formaldehyde sensitivity leading to the accumulation of replicative stress, DNA double-strand breaks, and quadriradial chromosomes, a typical feature of FA. After formaldehyde exposure, EXO1 is recruited to chromatin, protects DNA replication forks from degradation, and functions in parallel with the FA pathway to promote cell survival. In vitro, EXO1-mediated exonuclease activity is proficient in removing DPCs. Collectively, we show that EXO1 limits replication stress and DNA damage to counteract formaldehyde-induced genome instability.
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