Single-Stranded DNA Orchestrates an ATM-to-ATR Switch at DNA Breaks
Open accessAbstract
ATM and ATR are two master checkpoint kinases activated by double-stranded DNA breaks (DSBs). ATM is critical for the initial response and the subsequent ATR activation. Here we show that ATR activation is coupled with loss of ATM activation, an unexpected ATM-to-ATR switch during the biphasic DSB response. ATM is activated by DSBs with blunt ends or short single-stranded overhangs (SSOs). Surprisingly, the activation of ATM in the presence of SSOs, like that of ATR, relies on single- and double-stranded DNA junctions. In a length-dependent manner, SSOs attenuate ATM activation and potentiate ATR activation through a swap of DNA-damage sensors. Progressive resection of DSBs directly promotes the ATM-to-ATR switch in vitro. In cells, the ATM-to-ATR switch is driven by both ATM and the nucleases participating in DSB resection. Thus, single-stranded DNA orchestrates ATM and ATR to function in an orderly and reciprocal manner in two distinct phases of DSB response.
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An ATM-to-ATR switch during the biphasic double-strand break response was proposed in a study using mammalian cell lysates.
“Additionally, an ATM-to-ATR switch during the biphasic DSB response was proposed in a report using mammalian cell lysates [141].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [141]
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References 60 · Cited by 353
- Authors
- Shiotani, B., & Zou, L.
- Affiliations
- Harvard University (US)
- Corresponding author
- Zou, Lee
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 33
- Issue
- 5
- Pages
- 547-558
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2675165
- OpenAlex
- W2111420919
- Cited by
- 353
- References
- 60
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 11 · 2023: 15 · 2022: 14 · 2021: 32 · 2020: 21 · 2019: 19 · 2018: 19 · 2017: 19 · 2016: 14 · 2015: 18 · 2014: 29 · 2013: 31 · 2012: 26
- FWCI
- 13.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Susan G. Komen for the Cure
- University of Texas at Austin
- Susan G. Komen
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM076388, GM076388)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- ATM, ATR, single-stranded DNA, DNA double-strand breaks, DNA damage response, DNA resection, single-stranded overhangs, DNA damage sensor, checkpoint kinase, DNA junctions
- MeSH terms
- Checkpoint Kinase 1, MRE11 Homologue Protein, Carrier Proteins, DNA Repair, DNA-Binding Proteins, DNA, Single-Stranded, Endodeoxyribonucleases, Enzyme Activation, Exodeoxyribonucleases, HeLa Cells, Humans, Nuclear Proteins, Phosphorylation, Protein Kinases, Time Factors, Transfection, Protein Serine-Threonine Kinases, Acid Anhydride Hydrolases, Cell Cycle Proteins, Tumor Suppressor Proteins, RNA Interference, RNA, Small Interfering, DNA Repair Enzymes, Protein Kinase Inhibitors, DNA Breaks, Double-Stranded, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2
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