ATM couples replication stress and metabolic reprogramming during cellular senescence.
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.
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Katherine M
KM
Aird
Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Andrew J
AJ
Worth
Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Nathaniel W
NW
Snyder
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Joyce V
JV
Lee
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sharanya
S
Sivanand
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Qin
Q
Liu
Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ian A
IA
Blair
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Kathryn E
KE
Wellen
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: rzhang@wistar.org.
Rugang
R
Zhang
D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D002460:Cell Line; D065150:Cellular Reprogramming; D016922:Cellular Senescence; D004249:DNA Damage; D004261:DNA Replication; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D009711:Nucleotides / Q000378:metabolism; D010427:Pentose Phosphate Pathway; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D013312:Stress, Physiological; D013379:Substrate Specificity; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D009711:Nucleotides; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D005973:Glutamine; D005954:Glucosephosphate Dehydrogenase; D064007:Ataxia Telangiectasia Mutated Proteins; D005947:Glucose