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 journalArticlepeer-review

82 Scopus citations


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
Issue number6
StatePublished - May 12 2015

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology


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