ATM couples replication stress and metabolic reprogramming during cellular senescence

Area of Science:

• Cellular Biology
• Cancer Research
• Metabolism

Background:

• Replication stress from nucleotide deficiency is crucial in cancer initiation.
• Replication stress typically triggers cellular senescence, a tumor suppression mechanism.
• Senescence bypass is linked to cancer development and metabolic reprogramming.

Purpose of the Study:

• To investigate the role of metabolic reprogramming in cellular response to replication stress.
• To elucidate the function of ataxia telangiectasia mutated (ATM) in coupling replication stress and metabolism.

Main Methods:

• Investigated the effect of ATM inactivation on cellular senescence.
• Analyzed changes in deoxyribonucleotide triphosphate (dNTP) levels.
• Examined metabolic pathway alterations, including the pentose phosphate pathway (PPP), glucose, and glutamine consumption.
• Assessed the roles of p53 and c-MYC downstream of ATM.

Main Results:

• ATM inactivation bypasses senescence induced by replication stress.
• Deoxyribonucleotide triphosphate (dNTP) levels are restored upon ATM inactivation.
• Upregulation of the pentose phosphate pathway (PPP) via increased glucose-6-phosphate dehydrogenase (G6PD) activity and enhanced glucose/glutamine consumption were observed.
• These metabolic shifts were mediated by ATM-dependent suppression of p53 and upregulation of c-MYC.

Conclusions:

• ATM plays a central role in regulating cellular response to replication stress by shifting cellular metabolism.
• ATM status couples replication stress and metabolic reprogramming during the senescence process.
• Understanding this link provides insights into cancer development and potential therapeutic strategies.