A role for ATR in the DNA damage-induced phosphorylation of p53
Open accessAbstract
Phosphorylation at Ser-15 may be a critical event in the up-regulation and functional activation of p53 during cellular stress. In this report we provide evidence that the ATM-Rad3-related protein ATR regulates phosphorylation of Ser-15 in DNA-damaged cells. Overexpression of catalytically inactive ATR (ATRki) in human fibroblasts inhibited Ser-15 phosphorylation in response to gamma-irradiation and UV light. In gamma-irradiated cells, ATRki expression selectively interfered with late-phase Ser-15 phosphorylation, whereas ATRki blocked UV-induced Ser-15 phosphorylation in a time-independent manner. ATR phosphorylated p53 at Ser-15 and Ser-37 in vitro, suggesting that p53 is a target for phosphorylation by ATR in DNA-damaged cells.
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In human cells, ATM is activated by double-strand breaks such as those caused by ionizing radiation, while ATR is activated by RPA-coated ssDNA and mainly triggers checkpoint activation after UV irradiation or replication stress.
“In fact, ATM (Ataxia Telangiectasia Mutated) is activated by double-strand breaks (DSBs) caused, for example, by ionizing radiation (IR), while ATR (ATM and Rad3-Related) is activated by ssDNA coated with the RPA heterotrimeric complex and mainly triggers checkpoint activation after UV irradiation or replication-stress.”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [38]
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- Authors
- Tibbetts, R. S., Brumbaugh, K. M., Williams, J. M., Sarkaria, J. N., Cliby, W. A., Shieh, S.-Y., Taya, Y., Prives, C., & Abraham, R. T.
- Affiliations
- Duke University (US)
- Mayo Clinic (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1999-01-15
- Volume
- 13
- Issue
- 2
- Pages
- 152-157
- ISSN
- 0890-9369 (ISSN-L)
- PMC
- PMC316393
- OpenAlex
- W2155640249
- Cited by
- 1,046
- References
- 35
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 19 · 2023: 20 · 2022: 21 · 2021: 30 · 2020: 21 · 2019: 16 · 2018: 25 · 2017: 30 · 2016: 23 · 2015: 37 · 2014: 39 · 2013: 37 · 2012: 34
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA58316)
- National Cancer Institute (R37CA058316, CA76193, U01CA052995, CA-52995, R01CA076193, U19CA052995, T32CA009441, R01CA058316, CA 58316)
- 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 › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- ATR kinase, p53, DNA damage response, gamma irradiation, UV-induced DNA damage, p53 activation
- MeSH terms
- DNA Damage, DNA-Binding Proteins, Doxycycline, Fibroblasts, Gamma Rays, Humans, Mutation, Phosphorylation, Precipitin Tests, Proteins, Recombinant Fusion Proteins, Serine, Time Factors, Transfection, Tumor Cells, Cultured, Ultraviolet Rays, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Cell Cycle Proteins, K562 Cells, Tumor Suppressor Proteins, Ataxia Telangiectasia Mutated Proteins
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