Alkbh8 Regulates Selenocysteine-Protein Expression to Protect against Reactive Oxygen Species Damage.
Alkbh8 Regulates Selenocysteine-Protein Expression to Protect against Reactive Oxygen Species Damage.
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DOI：
10.1371/journal.pone.0131335
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Begley TJ
中科院分区：
文献类型：
--
作者：
Endres L;Begley U;Clark R;Gu C;Dziergowska A;Małkiewicz A;Melendez JA;Dedon PC;Begley TJ
环境和代谢来源的活性氧物种(ROS)可以破坏DNA、蛋白质和脂质，从而促进疾病。对基因表达的调控可以防止这种损害，包括增加转录、翻译和翻译后修饰。细胞对ROS的反应在疾病预防中发挥着重要作用，缺乏ROS与癌症、神经退化和衰老有关。在这里，我们详细描述了tRNA甲基转移酶Alkbh8对一组氧化应激反应酶的基础和损伤诱导的翻译调节。使用一种新的基因靶向敲除小鼠细胞系统，我们发现Alkbh8/胚胎成纤维细胞(MEF)显示出ROS水平升高，DNA和脂质损伤增加，以及细胞应激的特征。我们证明了Alkbh8是在ROS的诱导下被诱导的，并且是含硒半胱氨酸的ROS解毒酶的高效表达所必需的，这些酶属于谷胱甘肽过氧化物酶(GPX1、Gpx3、Gpx6和可能的Gpx4)和硫氧还蛋白还原酶(TrxR1)家族。我们还表明，作为对氧化应激的响应，tRNA修饰的5-甲氧羰甲基-2‘-O-甲基尿苷(Mcm5Um)在正常的MEF中增加，以驱动ROS解毒酶的表达，这种损伤诱导的tRNA重编程和停止密码子重新编码在Alkbh8-/-MEFS中被破坏。这些研究将Alkbh8和tRNA修饰定义为哺乳动物系统中细胞氧化应激反应的中心调节因子。此外，他们还强调了一种用于环境和癌症研究的新动物模型，并将翻译调控与防止DNA和脂肪损伤联系起来。
Environmental and metabolic sources of reactive oxygen species (ROS) can damage DNA, proteins and lipids to promote disease. Regulation of gene expression can prevent this damage and can include increased transcription, translation and post translational modification. Cellular responses to ROS play important roles in disease prevention, with deficiencies linked to cancer, neurodegeneration and ageing. Here we detail basal and damage-induced translational regulation of a group of oxidative-stress response enzymes by the tRNA methyltransferase Alkbh8. Using a new gene targeted knockout mouse cell system, we show that Alkbh8-/- embryonic fibroblasts (MEFs) display elevated ROS levels, increased DNA and lipid damage and hallmarks of cellular stress. We demonstrate that Alkbh8 is induced in response to ROS and is required for the efficient expression of selenocysteine-containing ROS detoxification enzymes belonging to the glutathione peroxidase (Gpx1, Gpx3, Gpx6 and likely Gpx4) and thioredoxin reductase (TrxR1) families. We also show that, in response to oxidative stress, the tRNA modification 5-methoxycarbonylmethyl-2′-O-methyluridine (mcm5Um) increases in normal MEFs to drive the expression of ROS detoxification enzymes, with this damage-induced reprogramming of tRNA and stop-codon recoding corrupted in Alkbh8-/- MEFS. These studies define Alkbh8 and tRNA modifications as central regulators of cellular oxidative stress responses in mammalian systems. In addition they highlight a new animal model for use in environmental and cancer studies and link translational regulation to the prevention of DNA and lipid damage.
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影响因子：
56.9
作者：
Cortez, D;Wang, Y;Elledge, SJ
通讯作者：
Elledge, SJ
影响因子：
14.9
作者：
Cavaluzzi, MJ;Borer, PN
通讯作者：
Borer, PN
影响因子：
6
作者：
Combs, GF;Clark, LC;Turnbull, BW
通讯作者：
Turnbull, BW
影响因子：
16
作者：
Begley, Ulrike;Dyavaiah, Madhu;Begley, Thomas J.
通讯作者：
Begley, Thomas J.
DOI：
10.1126/science.1151710
发表时间：
2007-11-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gerken T;Girard CA;Tung YC;Webby CJ;Saudek V;Hewitson KS;Yeo GS;McDonough MA;Cunliffe S;McNeill LA;Galvanovskis J;Rorsman P;Robins P;Prieur X;Coll AP;Ma M;Jovanovic Z;Farooqi IS;Sedgwick B;Barroso I;Lindahl T;Ponting CP;Ashcroft FM;O'Rahilly S;Schofield CJ
通讯作者：
Schofield CJ