The role of cysteines in the structure and function of OGG1.
The role of cysteines in the structure and function of OGG1.
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DOI：
10.1074/jbc.ra120.016126
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Alnajjar KS
中科院分区：
文献类型：
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作者：
Wang K;Maayah M;Sweasy JB;Alnajjar KS
8-氧鸟嘌呤糖基酶(OGG1)是一种碱基切除修复酶，负责识别和去除8-氧鸟嘌呤，8-氧鸟嘌呤是一种常见的氧化DNA修饰。OGG1可防止突变的积累，并调节各种氧化应激反应基因的转录。除了以DNA为靶标外，氧化应激还会影响OGG1等蛋白质本身，特别是半胱氨酸残基。以往的工作表明，OGG1的功能对氧化剂很敏感，OGG1的半胱氨酸残基是最有可能的氧化位点。由于OGG1在氧化应激下维持细胞内环境平衡方面起着不可或缺的作用，因此了解氧化剂对OGG1的影响以及半胱氨酸在其结构和功能中的作用是非常重要的。在这项研究中，我们通过突变和鉴定每个半胱氨酸残基来研究半胱氨酸残基在OGG1功能中的作用。我们的结果表明，OGG1中的半胱氨酸分为四种功能类型：(1)糖基酶活性(C146和C255)，(2)裂解酶活性(C140S，C163，C241和C253)，(3)结构稳定性(C253)和(4)那些未知功能的半胱氨酸(C28和C75)。这些结果表明，在氧化应激条件下，半胱氨酸可以被靶向修饰，从而改变OGG1的反应并影响其下游细胞功能。
8-Oxoguanine glycosylase (OGG1) is a base excision repair enzyme responsible for the recognition and removal of 8-oxoguanine, a commonly occurring oxidized DNA modification. OGG1 prevents the accumulation of mutations and regulates the transcription of various oxidative stress–response genes. In addition to targeting DNA, oxidative stress can affect proteins like OGG1 itself, specifically at cysteine residues. Previous work has shown that the function of OGG1 is sensitive to oxidants, with the cysteine residues of OGG1 being the most likely site of oxidation. Due to the integral role of OGG1 in maintaining cellular homeostasis under oxidative stress, it is important to understand the effect of oxidants on OGG1 and the role of cysteines in its structure and function. In this study, we investigate the role of the cysteine residues in the function of OGG1 by mutating and characterizing each cysteine residue. Our results indicate that the cysteines in OGG1 fall into four functional categories: those that are necessary for (1) glycosylase activity (C146 and C255), (2) lyase activity (C140S, C163, C241, and C253), and (3) structural stability (C253) and (4) those with no known function (C28 and C75). These results suggest that under conditions of oxidative stress, cysteine can be targeted for modifications, thus altering the response of OGG1 and affecting its downstream cellular functions.