ATM directs DNA damage responses and proteostasis via genetically separable pathways

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• The protein kinase ATM is crucial for DNA damage response and oxidative stress signaling.
• ATM deficiency leads to ataxia telangiectasia, a disorder with neurodegeneration, cancer, and aging.
• Distinct activation pathways for ATM by DNA damage and oxidative stress are not fully understood.

Purpose of the Study:

• To genetically separate ATM activation by DNA damage from activation by oxidative stress.
• To investigate the distinct cellular roles of ATM in response to these stimuli.
• To elucidate ATM's role in cellular metabolism, protein homeostasis, and disease.

Main Methods:

• Utilizing separation-of-function mutations to distinguish ATM activation mechanisms.
• Assessing cell viability, DNA damage response pathways (checkpoint activation, DNA end resection), mitochondrial function, and autophagy.
• Analyzing protein aggregation in cells expressing ATM variants.

Main Results:

• Deficient activation by DNA damage impaired cell viability and DNA repair.
• Loss of oxidative activation minimally impacted DNA damage outcomes but disrupted oxidative stress responses, mitochondrial function, and autophagy.
• ATM variants unable to activate via oxidative stress showed widespread protein aggregation.

Conclusions:

• ATM activation mechanisms directly influence its effects on cellular metabolism and DNA repair.
• ATM plays a critical role in managing oxidative stress responses and maintaining protein homeostasis.
• Understanding ATM activation is key to addressing ataxia telangiectasia and related aging phenotypes.