ATM Couples Replication Stress and Metabolic Reprogramming during Cellular Senescence

Katherine M. Aird, Andrew J. Worth, Nathaniel W. Snyder, Joyce V. Lee, Sharanya Sivanand, Qin Liu, Ian A. Blair, Kathryn E. Wellen, Rugang Zhang

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

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 ofcancer, 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 thepentose 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.

Original languageEnglish (US)
Pages (from-to)893-901
Number of pages9
JournalCell Reports
Volume11
Issue number6
DOIs
StatePublished - May 12 2015

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Ataxia Telangiectasia
Cell Aging
Up-Regulation
Nucleotides
Deoxyribonucleotides
Glucosephosphate Dehydrogenase
Metabolic Diseases
Glutamine
Neoplasms
Phosphates
Phenotype
Metabolism
Glucose
Restoration
Tumors

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Aird, K. M., Worth, A. J., Snyder, N. W., Lee, J. V., Sivanand, S., Liu, Q., ... Zhang, R. (2015). ATM Couples Replication Stress and Metabolic Reprogramming during Cellular Senescence. Cell Reports, 11(6), 893-901. https://doi.org/10.1016/j.celrep.2015.04.014
Aird, Katherine M. ; Worth, Andrew J. ; Snyder, Nathaniel W. ; Lee, Joyce V. ; Sivanand, Sharanya ; Liu, Qin ; Blair, Ian A. ; Wellen, Kathryn E. ; Zhang, Rugang. / ATM Couples Replication Stress and Metabolic Reprogramming during Cellular Senescence. In: Cell Reports. 2015 ; Vol. 11, No. 6. pp. 893-901.
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Aird, KM, Worth, AJ, Snyder, NW, Lee, JV, Sivanand, S, Liu, Q, Blair, IA, Wellen, KE & Zhang, R 2015, 'ATM Couples Replication Stress and Metabolic Reprogramming during Cellular Senescence', Cell Reports, vol. 11, no. 6, pp. 893-901. https://doi.org/10.1016/j.celrep.2015.04.014

ATM Couples Replication Stress and Metabolic Reprogramming during Cellular Senescence. / Aird, Katherine M.; Worth, Andrew J.; Snyder, Nathaniel W.; Lee, Joyce V.; Sivanand, Sharanya; Liu, Qin; Blair, Ian A.; Wellen, Kathryn E.; Zhang, Rugang.

In: Cell Reports, Vol. 11, No. 6, 12.05.2015, p. 893-901.

Research output: Contribution to journalArticle

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