ATM functions at the peroxisome to induce pexophagy in response to ROS

Zhang, Jiangwei; Tripathi, Durga Nand; Ji, Jing; Alexander, Angela; Kim, Jinhee; Powell, Reid T.; Dere, Ruhee; Tait-Mulder, Jacqueline; Lee, Ji-Hoon; Paull, Tanya T.; Pandita, Raj K.; Charaka, Vijaya; Pandita, Tej K.; Kastan, Michael B.; Walker, Cheryl L.

doi:10.1038/ncb3230

Cited by 340 publications

(341 citation statements)

References 62 publications

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“…While a number of cytoplasmic proteins have been shown to be phosphorylated after ATM activation by DNA-damaging agents (28,(42)(43)(44)(45)(46)(47)(48)(49)(50), the only direct evidence for activation in the cytoplasm has only recently been demonstrated (10). In that report, they show that ATM is localized to the peroxisome in agreement with earlier observations (11).…”

Section: (Supplementalsupporting

confidence: 82%

“…In this case the active form of ATM is not a monomer but rather a disulfide-linked, covalent dimer, and the suite of downstream substrates appears to be more limited than that activated by DNA double strand breaks (5). More recently, it has been reported that the peroxisome import receptor protein, PEX5, binds ATM and localizes it to peroxisomes (10). ATM had previously been localized to this organelle (11).…”

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confidence: 99%

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Reactive Oxygen Species (ROS)-Activated ATM-Dependent Phosphorylation of Cytoplasmic Substrates Identified by Large-Scale Phosphoproteomics Screen

Kozlov

Waardenberg

Engholm-Keller

et al. 2016

Molecular & Cellular Proteomics

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Ataxia-telangiectasia, mutated (ATM) protein plays a central role in phosphorylating a network of proteins in response to DNA damage. These proteins function in signaling pathways designed to maintain the stability of the genome and minimize the risk of disease by controlling cell cycle checkpoints, initiating DNA repair, and regulating gene expression. ATM kinase can be activated by a variety of stimuli, including oxidative stress. Here, we confirmed activation of cytoplasmic ATM by autophosphorylation at multiple sites. Then we employed a global quantitative phosphoproteomics approach to identify cytoplasmic proteins altered in their phosphorylation state in control and ataxia-telangiectasia (A-T) cells in response to oxidative damage. We demonstrated that ATM was activated by oxidative damage in the cytoplasm as well as in the nucleus and identified a total of 9,833 phosphorylation sites, including 6,686 high-confidence sites mapping to 2,536 unique proteins. A total of 62 differentially phosphorylated peptides were identified; of these, 43 were phosphorylated in control but not in A-T cells, and 19 varied in their level of phosphorylation. Motif enrichment analysis of phosphopeptides revealed that consensus ATM serine glutamine sites were overrepresented. When considering phosphorylation events, only observed in control cells (not observed in A-T cells), with predicted ATM sites phosphoSerine/phosphoThreonine glutamine, we narrowed this list to 11 candidate ATM-dependent cytoplasmic proteins. Two of these 11 were previously described as ATM substrates (HMGA1 and UIMCI/RAP80), another five were identified in a whole cell extract

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Section: (Supplementalsupporting

confidence: 82%

mentioning

confidence: 99%

Reactive Oxygen Species (ROS)-Activated ATM-Dependent Phosphorylation of Cytoplasmic Substrates Identified by Large-Scale Phosphoproteomics Screen

Kozlov

Waardenberg

Engholm-Keller

et al. 2016

Molecular & Cellular Proteomics

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“…Catalase activity is lower in ATM-deficient human cells compared to normal controls (71) and in ATM−/− mice where the deficit was reported specifically in the cerebellum (72), an important detail given the Purkinje cell specificity of the A-T disorder in humans. The ATM protein has also been reported to be associated with peroxisomes (52, 73), the location of catalase activity in human cells, which is perhaps relevant to the overall deficit in catalase function in cells lacking ATM.…”

Section: Discussionmentioning

confidence: 99%

ATM directs DNA damage responses and proteostasis via genetically separable pathways

et al. 2018

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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. Here, we genetically separated DNA damage activation of ATM from oxidative activation using separation-of-function mutations. We found that deficiency in ATM activation by Mre11-Rad50-Nbs1 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 ATM lacking oxidative activation generates 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 implicates ATM in the control of protein homeostasis.

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“…While some of these also include DNA strand breaks, other suggestions involve oxidative stress, mitochondrial dysfunction, and altered ATM cytoplasmic (non-DNA damage) functions (Eaton et al 2007;Guo et al 2010;ValentinVega et al 2012;Zhang et al 2015;Fang et al 2016). Currently, the important etiologic agents and the actual basis for cell loss that results in neurodegeneration remain uncertain.…”

Section: A-t and Atm: A Paradigm For Dna Damage-related Neurodegeneramentioning

confidence: 99%

Genome integrity and disease prevention in the nervous system

2017

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ATM functions at the peroxisome to induce pexophagy in response to ROS

Cited by 340 publications

References 62 publications

Reactive Oxygen Species (ROS)-Activated ATM-Dependent Phosphorylation of Cytoplasmic Substrates Identified by Large-Scale Phosphoproteomics Screen

Reactive Oxygen Species (ROS)-Activated ATM-Dependent Phosphorylation of Cytoplasmic Substrates Identified by Large-Scale Phosphoproteomics Screen

ATM directs DNA damage responses and proteostasis via genetically separable pathways

Genome integrity and disease prevention in the nervous system

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