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
Genotype-Phenotype Relationships in Ataxia-Telangiectasia and Variants
Shlomit Gilad,Luciana Chessa,Rami Khosravi,Pamela Russell,Yaron Galanty,Maria Piane,Richard A. Gatti,Timothy J. Jorgensen,Yosef Shiloh,Anat Bar-Shira +9 more
TL;DR: It is concluded that certain "A-T variant" phenotypes represent ATM mutations, including some of those without telangiectasia, which extends the range of phenotypes associated with ATM mutations.
Journal ArticleDOI
Deranged Calcium Signaling and Neurodegeneration in Spinocerebellar Ataxia Type 3
Xi Chen,Tie-Shan Tang,Huiping Tu,Huiping Tu,Omar L. Nelson,Mark A. Pook,Robert E. Hammer,Nobuyuki Nukina,Ilya Bezprozvanny +8 more
TL;DR: It is found that feeding SCA3-YAC-84Q transgenic mice with dantrolene, a clinically relevant stabilizer of intracellular Ca2+ signaling, improved their motor performance and prevented neuronal cell loss in pontine nuclei and substantia nigra regions.
Journal ArticleDOI
Initiation of meiotic recombination by formation of DNA double-strand breaks: mechanism and regulation
TL;DR: Recent findings pertaining to protein-protein interactions important for DSB formation, the mechanism of an early step in the processing of Spo11-generated DSBs, and regulation of D SB formation by protein kinases are reviewed.
Journal ArticleDOI
Serine ADP-Ribosylation Depends on HPF1
Juan José Bonfiglio,Pietro Fontana,Qi Zhang,Thomas Colby,Ian Gibbs-Seymour,Ilian Atanassov,Edward Bartlett,Roko Zaja,Ivan Ahel,Ivan Matic +9 more
TL;DR: It is reported that serine ADPr is strictly dependent on histone PARylation factor 1 (HPF1), a recently identified regulator of PARP-1, and proposed that O-linked protein AD Pr is the key signal in PARP/PARP-2-dependent processes that govern genome stability.
Journal ArticleDOI
A new method for high-resolution imaging of Ku foci to decipher mechanisms of DNA double-strand break repair.
TL;DR: A combination of RNase- and detergent-based preextraction with high-resolution microscopy allows the detection of Ku and other DNA repair proteins at single double-strand breaks in cells.