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
Causative Links between Protein Aggregation and Oxidative Stress: A Review
Elise Lévy,Nadine El Banna,Dorothée Baïlle,Amélie Heneman-Masurel,Sandrine Truchet,Human Rezaei,Meng-Er Huang,Vincent Béringue,Davy Martin,Laurence Vernis +9 more
TL;DR: This review aims at providing an update of the previously known functional links between oxidative stress and protein aggregation, thereby revisiting the long-established relationship between both processes.
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Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice.
Kenta Yamamoto,Yunyue Wang,Wenxia Jiang,Xiangyu Liu,Richard L. Dubois,Chyuan Sheng Lin,Thomas Ludwig,Christopher J. Bakkenist,Shan Zha +8 more
TL;DR: Expression of a kinase-deficient ATM protein leads to severe genomic instability and embryonic lethality.
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Complementary functions of ATM and H2AX in development and suppression of genomic instability
TL;DR: Mechanistically, severe genomic instability in the double-deficient cells is associated with a requirement for H2AX to repair oxidative DNA damage resulting from ATM deficiency and is discussed in the context of synergies between ATM and other repair factors.
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Mre11 regulates CtIP-dependent double-strand break repair by interaction with CDK2.
TL;DR: It is shown that, in human and mouse, Mre11 controls these events through a direct interaction with CDK2 that is required for CtIP phosphorylation and BRCA1 interaction in normally dividing cells.
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Identification and characterization of FUS/TLS as a new target of ATM.
TL;DR: The results identify FUS as a new target of the ATM-signalling pathway and strengthen the notion that FUS regulates genome stability, which appears to play a role in regulating genome stability.