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EXO1 and DNA2-mediated ssDNA gap expansion is essential for ATR activation and to maintain viability in BRCA1-deficient cells.
- Source :
-
Nucleic acids research [Nucleic Acids Res] 2024 Jun 24; Vol. 52 (11), pp. 6376-6391. - Publication Year :
- 2024
-
Abstract
- DNA replication faces challenges from DNA lesions originated from endogenous or exogenous sources of stress, leading to the accumulation of single-stranded DNA (ssDNA) that triggers the activation of the ATR checkpoint response. To complete genome replication in the presence of damaged DNA, cells employ DNA damage tolerance mechanisms that operate not only at stalled replication forks but also at ssDNA gaps originated by repriming of DNA synthesis downstream of lesions. Here, we demonstrate that human cells accumulate post-replicative ssDNA gaps following replicative stress induction. These gaps, initiated by PrimPol repriming and expanded by the long-range resection factors EXO1 and DNA2, constitute the principal origin of the ssDNA signal responsible for ATR activation upon replication stress, in contrast to stalled forks. Strikingly, the loss of EXO1 or DNA2 results in synthetic lethality when combined with BRCA1 deficiency, but not BRCA2. This phenomenon aligns with the observation that BRCA1 alone contributes to the expansion of ssDNA gaps. Remarkably, BRCA1-deficient cells become addicted to the overexpression of EXO1, DNA2 or BLM. This dependence on long-range resection unveils a new vulnerability of BRCA1-mutant tumors, shedding light on potential therapeutic targets for these cancers.<br /> (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Subjects :
- Humans
Cell Survival genetics
DNA Repair Enzymes metabolism
DNA Repair Enzymes genetics
DNA Damage
Ataxia Telangiectasia Mutated Proteins metabolism
Ataxia Telangiectasia Mutated Proteins genetics
DNA, Single-Stranded metabolism
DNA, Single-Stranded genetics
Exodeoxyribonucleases metabolism
Exodeoxyribonucleases genetics
DNA Replication genetics
BRCA1 Protein metabolism
BRCA1 Protein genetics
DNA Helicases metabolism
DNA Helicases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1362-4962
- Volume :
- 52
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Nucleic acids research
- Publication Type :
- Academic Journal
- Accession number :
- 38721777
- Full Text :
- https://doi.org/10.1093/nar/gkae317