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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Regulatory spine RS3 residue of protein kinases: a lipophilic bystander or a decisive element in the small-molecule kinase inhibitor binding?
TL;DR: In this paper , the role of regulatory spine residues in protein kinase inhibitor design is discussed, and the current knowledge of RS3, its relationship with the gatekeeper, and its role in protein inhibitor interactions is discussed.
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.
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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.
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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.
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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.