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Mec1 信号网络在介导复制、遗传毒性和蛋白毒性应激抗性中的多功能性。

Versatility of the Mec1 signaling network in mediating resistance to replication, genotoxic, and proteotoxic stresses.

机构信息

School of Medical Sciences and North West Cancer Research Institute, Bangor University, Bangor, LL57 2UW, UK.

出版信息

Curr Genet. 2019 Jun;65(3):657-661. doi: 10.1007/s00294-018-0920-y. Epub 2019 Jan 5.

DOI:10.1007/s00294-018-0920-y
PMID:30610294
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6510830/
Abstract

The ataxia-telangiectasia mutated/ATM and Rad3-related (ATM/ATR) family proteins are evolutionarily conserved serine/threonine kinases best known for their roles in mediating the DNA damage response. Upon activation, ATM/ATR phosphorylate numerous targets to stabilize stalled replication forks, repair damaged DNA, and inhibit cell cycle progression to ensure survival of the cell and safeguard integrity of the genome. Intriguingly, separation of function alleles of the human ATM and MEC1, the budding yeast ATM/ATR, were shown to confer widespread protein aggregation and acute sensitivity to different types of proteotoxic agents including heavy metal, amino acid analogue, and an aggregation-prone peptide derived from the Huntington's disease protein. Further analyses unveiled that ATM and Mec1 promote resistance to perturbation in protein homeostasis via a mechanism distinct from the DNA damage response. In this minireview, we summarize the key findings and discuss ATM/ATR as a multifaceted signalling protein capable of mediating cellular response to both DNA and protein damage.

摘要

共济失调毛细血管扩张突变/ATM 和 Rad3 相关（ATM/ATR）家族蛋白是进化上保守的丝氨酸/苏氨酸激酶，其在介导 DNA 损伤反应中的作用最为人所知。在被激活后，ATM/ATR 磷酸化大量靶标以稳定停滞的复制叉、修复受损的 DNA，并抑制细胞周期进程，以确保细胞的存活和基因组的完整性。有趣的是，人类 ATM 和 MEC1 的功能分离等位基因（芽殖酵母 ATM/ATR）被证明赋予了广泛的蛋白质聚集，并对不同类型的蛋白毒性物质（包括重金属、氨基酸类似物和源自亨廷顿病蛋白的易于聚集的肽）敏感。进一步的分析揭示，ATM 和 Mec1 通过一种与 DNA 损伤反应不同的机制促进对蛋白质平衡扰动的抗性。在这篇综述中，我们总结了关键发现，并讨论了 ATM/ATR 作为一种多功能信号蛋白，能够介导细胞对 DNA 和蛋白质损伤的反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/128b/6510830/e30e08b7a9ec/294_2018_920_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/128b/6510830/e30e08b7a9ec/294_2018_920_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/128b/6510830/e30e08b7a9ec/294_2018_920_Fig1_HTML.jpg

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