ATM Couples Replication Stress and Metabolic Reprogramming during Cellular Senescence
Open accessAbstract
Replication stress induced by nucleotide deficiency plays an important role in cancer initiation. Replication stress in primary cells typically activates the cellular senescence tumor-suppression mechanism. Senescence bypass correlates with development of cancer, a disease characterized by metabolic reprogramming. However, the role of metabolic reprogramming in the cellular response to replication stress has been little explored. Here, we report that ataxia telangiectasia mutated (ATM) plays a central role in regulating the cellular response to replication stress by shifting cellular metabolism. ATM inactivation bypasses senescence induced by replication stress triggered by nucleotide deficiency. This was due to restoration of deoxyribonucleotide triphosphate (dNTP) levels through both upregulation of the pentose phosphate pathway via increased glucose-6-phosphate dehydrogenase (G6PD) activity and enhanced glucose and glutamine consumption. These phenotypes were mediated by a coordinated suppression of p53 and upregulation of c-MYC downstream of ATM inactivation. Our data indicate that ATM status couples replication stress and metabolic reprogramming during senescence.
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Senescence induced by nucleotide deficiency causes aberrant DNA replication but can be overcome by ATM inactivation through restoration of glucose and glutamine consumption.
“Senescence induced by nucleotide deficiency causes aberrant DNA replication but can be overcome by ATM inactivation through restoration of glucose and glutamine consumption [220].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [220]
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References 39 · Cited by 113
- Authors
- Aird, K. M., Worth, A. J., Snyder, N. W., Lee, J. V., Sivanand, S., Liu, Q., Blair, I. A., Wellen, K. E., & Zhang, R.
- Affiliations
- The Wistar Institute (US)
- University of Pennsylvania (US)
- Corresponding author
- Zhang, Rugang
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 11
- Issue
- 6
- Pages
- 893-901
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4431925
- OpenAlex
- W1995580021
- Cited by
- 113
- References
- 39
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 12 · 2020: 14 · 2019: 13 · 2018: 9 · 2017: 11 · 2016: 15 · 2015: 3
- FWCI
- 9.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Cancer Institute (CA010815, R01CA174761, K99CA194309, T32CA9171-35, R01CA160331, R00CA194309, R21CA194973, P50CA174523, T32CA009171, P30CA010815, P30CA016520)
- National Institute of General Medical Sciences (T32GM008076)
- National Institute of Environmental Health Sciences (T32ES019851, P30ES013508)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- ATM, replication stress, cellular senescence, metabolic reprogramming, senescence bypass, pentose phosphate pathway, glucose-6-phosphate dehydrogenase, glutamine consumption, p53 suppression, c-Myc, tumor initiation, tumor suppression
- MeSH terms
- Cell Line, DNA Damage, DNA Replication, Glucose, Glucosephosphate Dehydrogenase, Glutamine, Humans, Nucleotides, Pentose Phosphate Pathway, Stress, Physiological, Substrate Specificity, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-myc, Cellular Senescence, Gene Knockdown Techniques, Ataxia Telangiectasia Mutated Proteins, Cellular Reprogramming
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