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A CRISPR-Cas9 screen identifies EXO1 as a formaldehyde resistance gene

Author

Listed:
  • Yuandi Gao

    (Laval University Cancer Research Center)

  • Laure Guitton-Sert

    (Laval University Cancer Research Center)

  • Julien Dessapt

    (Laval University Cancer Research Center)

  • Yan Coulombe

    (Laval University Cancer Research Center)

  • Amélie Rodrigue

    (Laval University Cancer Research Center)

  • Larissa Milano

    (Laval University Cancer Research Center)

  • Andréanne Blondeau

    (Laval University Cancer Research Center)

  • Nicolai Balle Larsen

    (University of Copenhagen)

  • Julien P. Duxin

    (University of Copenhagen)

  • Samer Hussein

    (Laval University Cancer Research Center)

  • Amélie Fradet-Turcotte

    (Laval University Cancer Research Center)

  • Jean-Yves Masson

    (Laval University Cancer Research Center)

Abstract

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.

Suggested Citation

  • 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-Turcott, 2023. "A CRISPR-Cas9 screen identifies EXO1 as a formaldehyde resistance gene," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35802-y
    DOI: 10.1038/s41467-023-35802-y
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    References listed on IDEAS

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