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Distinct but Concerted Roles of ATR, DNA-PK, and Chk1 in Countering Replication Stress during S Phase
Open accessAbstract
The ATR-Chk1 pathway is critical for DNA damage responses and cell-cycle progression. Chk1 inhibition is more deleterious to cycling cells than ATR inhibition, raising questions about ATR and Chk1 functions in the absence of extrinsic replication stress. Here we show that a key role of ATR in S phase is to coordinate RRM2 accumulation and origin firing. ATR inhibitor (ATRi) induces massive ssDNA accumulation and replication catastrophe in a fraction of early S-phase cells. In other S-phase cells, however, ATRi induces moderate ssDNA and triggers a DNA-PK and Chk1-mediated backup pathway to suppress origin firing. The backup pathway creates a threshold such that ATRi selectively kills cells under high replication stress, whereas Chk1 inhibitor induces cell death at a lower threshold. The levels of ATRi-induced ssDNA correlate with ATRi sensitivity in a panel of cell lines, suggesting that ATRi-induced ssDNA could be predictive of ATRi sensitivity in cancer cells.
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Self-citation
Metadata
- Authors
- Buisson, R., Boisvert, J. L., Benes, C. H., & Zou, L.
- Affiliations
- Harvard University (US)
- Corresponding author
- Zou, Lee
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 59
- Issue
- 6
- Pages
- 1011-1024
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4575890
- OpenAlex
- W1855851918
- Cited by
- 316
- References
- 72
- Citations by year
- 2026: 27 · 2025: 14 · 2024: 16 · 2023: 27 · 2022: 33 · 2021: 37 · 2020: 38 · 2019: 30 · 2018: 38 · 2017: 29 · 2016: 25 · 2015: 2
- FWCI
- 13.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Wellcome Trust (102696)
- National Institute of General Medical Sciences (R01GM076388, GM076388)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- ATR, DNA-dependent protein kinase, Chk1, replication stress, S phase, DNA damage response, RRM2, replication origin firing, single-stranded DNA, replication catastrophe, cancer cell lines
- MeSH terms
- Checkpoint Kinase 1, DNA Damage, DNA Replication, DNA, Single-Stranded, Humans, Nuclear Proteins, Phosphorylation, Protein Kinases, Protein Processing, Post-Translational, Ribonucleoside Diphosphate Reductase, Stress, Physiological, S Phase, Replication Origin, Cell Line, Tumor, DNA-Activated Protein Kinase, Ataxia Telangiectasia Mutated Proteins
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