SIRT7的稳定性与DNA损伤修复的机制研究

项目名称： SIRT7的稳定性与DNA损伤修复的机制研究

项目编号： No.81472627

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王海英

作者单位： 北京大学

项目金额： 72万元

中文摘要： Sirtuins是哺乳动物中Sir2的类似物，共有7个成员。SIRT7 是该家族唯一定位于核仁的蛋白质，它的生理功能尚不明确。越来越多的发现把它置于染色质修饰，代谢和肿瘤调控通络的十字路口上。因此也是很有前景的药物靶点。间接证据提示SIRT7可能参与DNA损伤修复。我们前期工作发现：（1） SIRT7 在DNA损伤的刺激下会发生剂量和时间依赖性的减少（2）SIRT7减少不是转录水平下降，而是蛋白质发生降解。（3）蛋白酶体抑制剂MG132能抑制DNA损伤导致的SIRT7降解。（4） RNAi敲除SIRT7，发现组蛋白H3K36me2减少。这些结果进一步表明SIRT7的稳定性在DNA损伤修复中发挥作用。本课题将以前期工作基础，深入探讨SIRT7参与DNA损伤修复的分子机制。为以SIRT7为靶点的药物开发提供新思路，为临床肿瘤治疗提供新的途径。

中文关键词： C08_结；直肠肿瘤；SIRT7；蛋白质稳定性；DNA；损伤修复

英文摘要： Sirtuins，mammalian analogs of Sir2 in yeast, which contain seven members. SIRT7 is uniquely positioned in nucleolus, and its physiological function is not clear. Growing evidence places SIRT7 at crossroads of chromatin modification,metabolic and tumor regulatory pathways. Thus, SIRT7 is a promising pharmacologic target. Indirect evidence suggests that SIRT7 may be involved in DNA damage repair. Our previous work found that: (1) SIRT7 occurs decrease in dose- and time-dependent manner in response to DNA damage state. (2)SIRT7 reduction is not from the decrease of transcription, but the protein degradation. (3)The proteasome inhibitor MG132 inhibits SIRT7 degradation caused by DNA damage. (4) Knock down SIRT7 with RNAi,histone H3K36me2 was decreased. These results further indicate that the stability of SIRT7 play a role in DNA damage repair. Based on preliminary work, we will further explore the molecular mechanisms of SIRT7 is involved in DNA damage repair. This work will provide new ideas for drug development targeting SIRT7 and a new way for clinical cancer therapy.

英文关键词： SIRT7;protein stabalization;DNA damage repair