当前位置: X-MOL 学术Nat. Rev. Mol. Cell Biol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Cellular functions of the protein kinase ATM and their relevance to human disease
Nature Reviews Molecular Cell Biology ( IF 81.3 ) Pub Date : 2021-08-24 , DOI: 10.1038/s41580-021-00394-2
Ji-Hoon Lee 1 , Tanya T Paull 1
Affiliation  

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.



中文翻译:

蛋白激酶 ATM 的细胞功能及其与人类疾病的相关性

蛋白激酶共济失调毛细血管扩张突变 (ATM) 是双链 DNA 断裂 (DSB) 信号和应激反应的主要调节器。三十年来,人们对 ATM 进行了广泛的研究,以阐明其在 DNA 损伤反应 (DDR) 和共济失调毛细血管扩张症 (AT) 发病机制中的作用,这是一种由 ATM 缺失引起的人类神经退行性疾病。尽管数百种蛋白质已被确定为 ATM 磷酸化目标,并且已确定该激酶的许多重要作用,但仍不清楚 ATM 缺乏如何导致早发性小脑变性,这在所有 AT 个体中都很常见。最近的研究表明 ATM 缺陷与其他小脑特异性神经系统疾病之间存在联系,以及与更常见的神经退行性疾病存在更广泛的相似之处。在这篇综述中,我们讨论了最近对 ATM 调控的结构见解,以及 AT 表型的可能病因,包括活性氧、线粒体功能障碍、转录改变、R 环代谢和选择性剪接、细胞蛋白质稳态和代谢缺陷以及潜在的致病性超聚(ADP-核糖基)化的作用。

更新日期:2021-08-25
down
wechat
bug