Journal ArticleDOI
Cellular functions of the protein kinase ATM and their relevance to human disease.
Ji-Hoon Lee,Tanya T. Paull +1 more
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The protein kinase ataxia telangiectasia mutated (ATM) is a master regulator of double-strand DNA break (DSB) signalling and stress responses as discussed by the authors.Abstract:
The protein kinase ataxia telangiectasia mutated (ATM) is a master regulator of double-strand DNA break (DSB) signalling and stress responses. For three decades, ATM has been investigated extensively to elucidate its roles in the DNA damage response (DDR) and in the pathogenesis of ataxia telangiectasia (A-T), a human neurodegenerative disease caused by loss of ATM. Although hundreds of proteins have been identified as ATM phosphorylation targets and many important roles for this kinase have been identified, it is still unclear how ATM deficiency leads to the early-onset cerebellar degeneration that is common in all individuals with A-T. Recent studies suggest the existence of links between ATM deficiency and other cerebellum-specific neurological disorders, as well as the existence of broader similarities with more common neurodegenerative disorders. In this Review, we discuss recent structural insights into ATM regulation, and possible aetiologies of A-T phenotypes, including reactive oxygen species, mitochondrial dysfunction, alterations in transcription, R-loop metabolism and alternative splicing, defects in cellular proteostasis and metabolism, and potential pathogenic roles for hyper-poly(ADP-ribosyl)ation.read more
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DNA repair defects in cancer and therapeutic opportunities
Jessica L Hopkins,Li Lan,Lee Zou +2 more
TL;DR: The major classes of DNA repair and damage signaling defects in cancer, the genomic instability that they give rise to, and therapeutic strategies to exploit the resulting vulnerabilities are reviewed.
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Histone H2A variants: Diversifying chromatin to ensure genome integrity.
TL;DR: A growing body of work is now providing a clearer picture on the involvement and mechanistic basis of H2A variant contribution to genome integrity as discussed by the authors , and how alterations in these pathways contribute to human diseases including cancer.
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DNA Damage, Defective DNA Repair, and Neurodegeneration in Amyotrophic Lateral Sclerosis
Anna Konopka,Julie D. Atkin +1 more
TL;DR: Recent evidence highlighting DNA damage and defective DNA repair as an important mechanism linked to neurodegeneration in ALS is reviewed.
Journal ArticleDOI
Mitochondrial DNA damage as driver of cellular outcomes
TL;DR: In this article , the mtDNA damage contributes to cellular dysfunction and health outcomes, including neurodegenerative diseases, diabetes, cancer, and autoimmunity, which is a hallmark of aging and is involved in a number of different disorders.
Journal ArticleDOI
ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer
Sabrina Putti,Alessandro Giovinazzo,Matilde Merolle,Maria Laura Falchetti,Manuela Pellegrini +4 more
TL;DR: In this paper, the authors summarized the multiple discoveries from humans and mouse models on ATM mutations, focusing into the inactive versus null ATM and highlighted a high percentage of ATM mutations in the phosphoinositide 3-kinase domain, mostly in cancer cells resistant to classical therapy.
References
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Journal ArticleDOI
Reducing Mitochondrial ROS Improves Disease-related Pathology in a Mouse Model of Ataxia-telangiectasia
Anthony D. D’Souza,Ian A. Parish,Diane S. Krause,Susan M. Kaech,Susan M. Kaech,Gerald S. Shadel +5 more
TL;DR: Proof-of-principle that reducing mitochondrial ROS production per se may be therapeutic for the disease A-T is provided, which may have advantages compared with more general antioxidant strategies.
Journal ArticleDOI
TDP1 serine 81 promotes interaction with DNA ligase IIIalpha and facilitates cell survival following DNA damage.
TL;DR: A novel mechanism for regulating TDP1 function in mammalian cells that is not directly related to its enzymatic activity is identified.
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ATM regulates NF-κB-dependent immediate-early genes via RelA Ser 276 phosphorylation coupled to CDK9 promoter recruitment
Ling Fang,Sanjeev Choudhary,Yingxin Zhao,Chukwudi B. Edeh,Chunying Yang,Istvan Boldogh,Allan R. Brasier +6 more
TL;DR: It is concluded that ATM is a nuclear damage-response signal modulator of TNF-induced NF-κB activation that plays a key scaffolding role in IκBα degradation and RelA Ser 276 phosphorylation.
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Activation of PARP by oxidative stress induced by β-amyloid: implications for Alzheimer's disease.
Rosella Abeti,Michael R. Duchen +1 more
TL;DR: The relationship between AD and PARP-1 is reviewed, and the role played by astrocytes in neuronal death is explored, a step towards a greater understanding of the pathophysiology of this devastating disease with the potential to explore novel therapeutic targets.
Journal ArticleDOI
ATM and ATR pathways signal alternative splicing of Drosophila TAF1 pre-mRNA in response to DNA damage.
TL;DR: Findings suggest that inducible TAF1 alternative splicing is a mechanism to regulate transcription in response to developmental or DNA damage signals and provide the first evidence that the ATM/CHK2 and ATR/ CHK1 signaling pathways control gene expression by regulatingAlternative splicing.