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ATM couples replication stress and metabolic reprogramming during cellular senescence.


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.

SUBMITTER: Aird KM 

PROVIDER: S-EPMC4431925 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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ATM couples replication stress and metabolic reprogramming during cellular senescence.

Aird Katherine M KM   Worth Andrew J AJ   Snyder Nathaniel W NW   Lee Joyce V JV   Sivanand Sharanya S   Liu Qin Q   Blair Ian A IA   Wellen Kathryn E KE   Zhang Rugang R  

Cell reports 20150430 6


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 c  ...[more]

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