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
Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency
TL;DR: In this article, it was shown that the insoluble protein species arise from intrinsically disordered proteins associating with PAR-associated genomic sites in ATM-deficient cells, and the lesions implicated in this process are single-strand DNA breaks dependent on reactive oxygen species, transcription, and R-loops.
Journal ArticleDOI
Ataxia telangiectasia mutated-dependent regulation of topoisomerase II alpha expression and sensitivity to topoisomerase II inhibitor.
Hiroyuki Tamaichi,Masaki Sato,Andrew C.G. Porter,Toshiaki Shimizu,Shuki Mizutani,Masatoshi Takagi +5 more
TL;DR: The findings suggest that ATM‐dependent TOP2A modification is required for proper regulation of TOP2 stability and subsequently of the sensitivity to TOP2 inhibitor, which has clinically important implications for the pathogenesis of infantile acute leukemia as well as treatment‐associated secondary leukemia following exposure toTOP2 inhibitors.
Journal ArticleDOI
Comparison of Selected Parameters of Redox Homeostasis in Patients with Ataxia-Telangiectasia and Nijmegen Breakage Syndrome
Barbara Pietrucha,Edyta Heropolitańska-Pliszka,Mateusz Maciejczyk,Halina Car,Jolanta Sawicka-Powierza,Radosław Motkowski,Joanna Karpińska,Marta Hryniewicka,Anna Zalewska,Małgorzata Pac,Beata Wolska-Kusnierz,Ewa Bernatowska,Bożena Mikołuć +12 more
TL;DR: A need for diagnosing oxidative stress in patients with ataxia-telangiectasia and Nijmegen breakage syndrome as a potential disease biomarker is indicated and decreased CoQ10 concentration in NBS and AT indicates a need for possible supplementation.
Journal ArticleDOI
Oxidative stress modulates rearrangement of endoplasmic reticulum-mitochondria contacts and calcium dysregulation in a Friedreich's ataxia model.
Laura R. Rodríguez,Pablo Calap-Quintana,Tamara Lapeña-Luzón,Federico V. Pallardó,Stephan Schneuwly,Juan A. Navarro,Pilar Gonzalez-Cabo +6 more
TL;DR: This work describes for the first time frataxin as a member of the protein network of MAMs, where interacts with two of the main proteins implicated in endoplasmic reticulum-mitochondria communication.
Journal ArticleDOI
Targeting the Ataxia Telangiectasia Mutated-null phenotype in chronic lymphocytic leukemia with pro-oxidants.
Angelo Agathanggelou,Victoria J Weston,Tracey Perry,Nicholas J. Davies,Anna Skowronska,Daniel T. Payne,John S. Fossey,Ceri E. Oldreive,Wenbin Wei,Guy Pratt,Helen Parry,David Oscier,Steve J. Coles,Paul S. Hole,Richard Lawrence Darley,Michael McMahon,John D. Hayes,Paul Moss,Grant S. Stewart,A. Malcolm R. Taylor,Tatjana Stankovic +20 more
TL;DR: It is found that defective redox-homeostasis represents an attractive therapeutic target for Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia and was mediated by a p53- and caspase-independent mechanism associated with apoptosis inducing factor activity.