SIRT1对早老综合症RTS致病蛋白RecQ4的功能调节

项目名称： SIRT1对早老综合症RTS致病蛋白RecQ4的功能调节

项目编号： No.81471405

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： 罗建沅

作者单位： 北京大学

项目金额： 80万元

中文摘要： RT综合症是一种未老先衰和癌症易感的遗传疾病，其致病基因RecQ4蛋白的研究对于衰老领域是非常重要的。SIRT1也是与衰老直接相关的蛋白，作为都与衰老相关的两个蛋白的结合，提示我们这两个蛋白极有可能互相作用共同调节人体及细胞的衰老。尽管RecQ4蛋白在DNA复制起始过程中起到很重要的作用，但其解旋酶在细胞中的精确调节和作用一直未被发现。我们在先期研究中发现RecQ4能够与SIRT1结合并被其去乙酰化。本项目将在此基础上，继续如下内容研究：1）证明RecQ4的乙酰化是DNA复制中必须的。2）调查RecQ4乙酰化在DNA复制过程中的动态调节。3）SIRT1 调节RecQ4 在S期DNA复制中的时间分布和乙酰化的调节功能。4）研究RecQ4 乙酰化对DNA复制的时机的调节。5）调查乙酰化对RecQ4解旋酶活性的调节。6）RecQ4乙酰化及SIRT1的去乙酰化在细胞复制性衰老过程中的功能。

中文关键词： 衰老机制；蛋白质乙酰化；DNA复制；RT综合症；RecQ4基因

英文摘要： Mutations in RecQ4 gene are responsible for Rothmund-Thomson syndrome (RTS), a severe autosomal recessive genetic disorder causing premature aging and predisposition to specific cancers. SIRT1, a NAD-dependent histone deacetylase, has been proved to extend life span in yeast and C. elegans. it has also been found regulating premature cellular senescence induced by the tumor suppressors PML and p53. Our preliminary studies demonstrated that RecQ4 can be acetylated both in vitro and in vivo. RecQ4 can interact with SIRT1 and SIRT1 can deacetylate RecQ4 in cells. Based on these observations, the overall objective of this application is to elucidate the molecular mechanism of this RecQ4 acetylation and deacetylation pathway during DNA replication and further effect on cellular senescence. To achieve this goal,We will 1) Demonstrate the acetylation of RecQ4 protein is an essential event in DNA replication. 2) Investigate the dynamic regulation of RecQ4 acetylation in DNA replication in S phase. 3) Elucidate the role of SIRT1 in regulating of RecQ4 temporal distribution and acetylation during DNA replication in S phase. 4) Study the acetylation of RecQ4 in regulating DNA replication timing. 5) Investigate the acetylation of RecQ4 in regulating its enzymatic activities. 6) Test the role of RecQ4 acetylation and deacetylation pathway in cellular senescence.

英文关键词： Aging mechanism;protein acetylation;DNA replication;Rothmund-Thomson syndrome;RecQ4 gene