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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TLDR
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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Journal ArticleDOI
CHK2 Promotes Metabolic Stress-Induced Autophagy through ULK1 Phosphorylation
Ran Guo,Shan-Shan Wang,Xiaoyou Jiang,Ye Zhang,Yongming Luo,Hongxin Cui,Qiqiang Guo,Liu Cao,X. C. Xie +8 more
TL;DR: It is demonstrated that the ATM/CHK2/ULK1 axis initiates an autophagic adaptive response by sensing ROS, and it protects cells from metabolic stress-induced cellular damage.
Journal ArticleDOI
Central Nervous System Distribution of the Ataxia-Telangiectasia Mutated Kinase Inhibitor AZD1390: Implications for the Treatment of Brain Tumors
Surabhi Talele,Wenjuan Zhang,Jiajia Chen,Shiv K. Gupta,Danielle M. Burgenske,Jann N. Sarkaria,William F. Elmquist +6 more
TL;DR: It is shown that efflux mediated by P-glycoprotein (P-gp) limits central nervous system (CNS) distribution of AZD1390 and that there are no distributional differences within anatomical regions of CNS.
Journal ArticleDOI
The host tRNA epitranscriptome: A new player in RNA virus infections
TL;DR: In this article , the authors proposed that this feature is shared by multiple RNA viruses and that the involved tRNA modifying enzymes represent promising novel targets for the development of broad-spectrum antivirals.
Journal ArticleDOI
ATM orchestrates ferritinophagy and ferroptosis by phosphorylating NCOA4
TL;DR: In this paper , the Ser/Thr protein kinase ATM, the major sensor of DNA double-strand break damage, is indispensable for ferroptosis execution, and pharmacological inhibition or genetic ablation of ATM significantly antagonizes the enzyme.
Journal ArticleDOI
A familial case of Louis–Bar syndrome
TL;DR: Ataxia-telangiectasia represents a typical syndromic form of primary immunodeficiencies and is characterized by a significant diagnostic delay, which was demonstrated in this case report.
References
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Journal ArticleDOI
The DNA-damage response in human biology and disease
Stephen P. Jackson,Jiri Bartek +1 more
TL;DR: The authors' improving understanding of DNA-damage responses is providing new avenues for disease management, and these responses are biologically significant because they prevent diverse human diseases.
Journal ArticleDOI
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
TL;DR: It is shown that ATM is held inactive in unirradiated cells as a dimer or higher-order multimer, with the kinase domain bound to a region surrounding serine 1981 that is contained within the previously described ‘FAT’ domain.
Journal ArticleDOI
Biomolecular condensates: organizers of cellular biochemistry
TL;DR: This work has shown that liquid–liquid phase separation driven by multivalent macromolecular interactions is an important organizing principle for biomolecular condensates and has proposed a physical framework for this organizing principle.
Journal ArticleDOI
ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage
Shuhei Matsuoka,Bryan A. Ballif,Agata Smogorzewska,Agata Smogorzewska,E. Robert McDonald,Kristen E. Hurov,Ji Luo,Corey E. Bakalarski,Zhenming Zhao,Nicole L. Solimini,Yaniv Lerenthal,Yosef Shiloh,Steven P. Gygi,Stephen J. Elledge +13 more
TL;DR: A large-scale proteomic analysis of proteins phosphorylated in response to DNA damage on consensus sites recognized by ATM and ATR is performed and more than 900 regulated phosphorylation sites encompassing over 700 proteins are identified.
Journal ArticleDOI
A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation
Avinash Patel,Hyun O. Lee,Louise Jawerth,Shovamayee Maharana,Marcus Jahnel,Marco Y. Hein,Stoyno S. Stoynov,Julia Mahamid,Shambaditya Saha,Titus M. Franzmann,Andrej Pozniakovski,Ina Poser,Nicola Maghelli,Loic Royer,Martin Weigert,Eugene W. Myers,Stephan W. Grill,David N. Drechsel,Anthony A. Hyman,Simon Alberti +19 more
TL;DR: It is proposed that liquid-like compartments carry the trade-off between functionality and risk of aggregation and that aberrant phase transitions within liquid- like compartments lie at the heart of ALS and, presumably, other age-related diseases.