Research ArticleDNA damage

ATM directs DNA damage responses and proteostasis via genetically separable pathways

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Sci. Signal.  09 Jan 2018:
Vol. 11, Issue 512, eaan5598
DOI: 10.1126/scisignal.aan5598

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The many roles of ATM

The kinase ATM is classically known for its role in coordinating the response to DNA damage. DNA damage is caused by various intracellular and extracellular stimuli, including oxidative stress and free radicals. Lee et al. found critical amino acid residues that enable ATM to coordinate a response to DNA damage that is independent of its response to oxidative stress. Activation of ATM by either pathway promoted mitochondrial function and autophagy, thus mediating cell survival through metabolic changes. ATM activation via oxidative stress additionally promoted the clearance of toxic protein aggregates. These findings expand the roles of ATM and suggest that the loss of ATM function, such as in the neurodegenerative disease ataxia telangiectasia (A-T), causes broader cellular stress than that limited to a defective DNA damage response.


The protein kinase ATM is a master regulator of the DNA damage response but also responds directly to oxidative stress. Loss of ATM causes ataxia telangiectasia, a neurodegenerative disorder with pleiotropic symptoms that include cerebellar dysfunction, cancer, diabetes, and premature aging. We genetically separated the activation of ATM by DNA damage from that by oxidative stress using separation-of-function mutations. We found that deficient activation of ATM by the Mre11-Rad50-Nbs1 complex and DNA double-strand breaks resulted in loss of cell viability, checkpoint activation, and DNA end resection in response to DNA damage. In contrast, loss of oxidative activation of ATM had minimal effects on DNA damage–related outcomes but blocked ATM-mediated initiation of checkpoint responses after oxidative stress and resulted in deficiencies in mitochondrial function and autophagy. In addition, expression of a variant ATM incapable of activation by oxidative stress resulted in widespread protein aggregation. These results indicate a direct relationship between the mechanism of ATM activation and its effects on cellular metabolism and DNA damage responses in human cells and implicate ATM in the control of protein homeostasis.

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