Regulation of nucleotide excision repair activity by transcriptional and post-transcriptional control of the XPA protein.
Regulation of nucleotide excision repair activity by transcriptional and post-transcriptional control of the XPA protein.
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DOI：
10.1093/nar/gkq1318
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发表时间：
2011-04
影响因子：
14.9
通讯作者：
Sancar A
中科院分区：
文献类型：
--
作者：
Kang TH;Reardon JT;Sancar A
XPA（着色性干皮A）蛋白是人类核苷酸切除修复系统的六个核心因子之一。在这项研究中，我们发现XPA在所有测试的人类细胞系中都是一个限速因子，包括正常的人类成纤维细胞系。XPA的水平在转录水平上受分子昼夜节律钟的控制，在翻译后水平上受HECT结构域家族E3泛素连接酶HERC2的控制。下调HERC2稳定XPA可适度增强切除修复活性。相反，siRNA对XPA的下调会与XPA水平成比例地降低切除修复活性。DNA损伤可抑制XPA的泛素化和蛋白水解，从而促进该蛋白与染色质紧密结合并与HERC2 E3连接酶分离。最后，与最近的报道一致，我们发现XPA在翻译后被乙酰化修饰。然而，与之前的说法相反，我们发现在小鼠肝脏中只有一小部分XPA被乙酰化，并且在两种人类细胞系中SIRT1去乙酰化酶的下调并不影响整体修复率。总的来说，这些数据表明XPA是切除修复的一个限制因素，其水平受生物钟、泛素-蛋白酶体系统和DNA损伤的协调调节。
The XPA (Xeroderma pigmentosum A) protein is one of the six core factors of the human nucleotide excision repair system. In this study we show that XPA is a rate-limiting factor in all human cell lines tested, including a normal human fibroblast cell line. The level of XPA is controlled at the transcriptional level by the molecular circadian clock and at the post-translational level by a HECT domain family E3 ubiquitin ligase called HERC2. Stabilization of XPA by downregulation of HERC2 moderately enhances excision repair activity. Conversely, downregulation of XPA by siRNA reduces excision repair activity in proportion to the level of XPA. Ubiquitination and proteolysis of XPA are inhibited by DNA damage that promotes tight association of the protein with chromatin and its dissociation from the HERC2 E3 ligase. Finally, in agreement with a recent report, we find that XPA is post-translationally modified by acetylation. However, contrary to the previous claim, we find that in mouse liver only a small fraction of XPA is acetylated and that downregulation of SIRT1 deacetylase in two human cell lines does not affect the overall repair rate. Collectively, the data reveal that XPA is a limiting factor in excision repair and that its level is coordinately regulated by the circadian clock, the ubiquitin–proteasome system and DNA damage.
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影响因子：
16
作者：
Fan, Wei;Luo, Jianyuan
通讯作者：
Luo, Jianyuan
影响因子：
2.1
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作者：
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作者：
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作者：
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