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Cell Rep. 2015 May 12;11(6):893-901. doi: 10.1016/j.celrep.2015.04.014. Epub 2015 Apr 30.

ATM couples replication stress and metabolic reprogramming during cellular senescence.

Author information

1
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
2
Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
4
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
5
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: rzhang@wistar.org.

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 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.

PMID:
25937285
PMCID:
PMC4431925
DOI:
10.1016/j.celrep.2015.04.014
[Indexed for MEDLINE]
Free PMC Article

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