ATR signaling can drive cells into senescence in the absence of DNA breaks
Open accessAbstract
The ATR kinase is a key transducer of “replicative stress,” the type of genomic damage that has been postulated to be induced by oncogenes. Here we describe a cellular system in which we can unleash ATR activity at will, in the absence of any actual damage or additional signaling pathways triggered by DNA breaks. We demonstrate that activating ATR is sufficient to promote cell cycle arrest and, if persistent, triggers p53-dependent but Ink4a/ARF-independent senescence. Moreover, we show that an ectopic activation of ATR leads to a G1/S arrest in ATM −/− cells, providing the first evidence of functional complementation of ATM deficiency by ATR. Our system provides a novel platform for the study of the specific functions of ATR signaling and adds evidence for the tumor-suppressive potential of the DNA damage response.
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DDR-independent senescence has been reported in some experimental conditions where p16, p38MAPK, or ATR is constitutively activated or Pten is completely lost.
“Of note, DDR-independent senescence has also been reported in some experimental conditions where p16, p38MAPK, or ATR is constitutively activated or tumor suppressor Pten is completely lost (Toledo et al. 2008; Rodier et al. 2009; Alimonti et al. 2010; Freund et al. 2011).”
From Cellular senescence and its effector programs (2014) · cites this paper as Toledo et al. 2008
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References 41 · Cited by 183
- Authors
- Toledo, L. I., Murga, M., Gutierrez-Martinez, P., Soria, R., & Fernandez-Capetillo, O.
- Affiliations
- Spanish National Cancer Research Centre (ES)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2008-02-01
- Volume
- 22
- Issue
- 3
- Pages
- 297-302
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2216689
- OpenAlex
- W2146364516
- Cited by
- 183
- References
- 41
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 8 · 2023: 6 · 2022: 7 · 2021: 7 · 2020: 10 · 2019: 8 · 2018: 10 · 2017: 10 · 2016: 12 · 2015: 12 · 2014: 10 · 2013: 10 · 2012: 13
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Swiss Bridge Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- ATR kinase, replicative stress, cellular senescence, DNA damage response, Ink4a/Arf, G1/S cell cycle arrest, ATM deficiency, functional complementation, tumor suppression
- MeSH terms
- Animals, Cell Cycle, Cell Line, Transformed, DNA-Binding Proteins, Enzyme Activation, Humans, Signal Transduction, Tumor Suppressor Protein p53, Cellular Senescence, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Cyclin-Dependent Kinase Inhibitor p16, Tumor Suppressor Proteins, Cell Line, Tumor, Mice, DNA Breaks, Ataxia Telangiectasia Mutated Proteins
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