长链非编码RNA在RNA结合蛋白TLS介导的DNA修复中作用机制的研究

项目名称： 长链非编码RNA在RNA结合蛋白TLS介导的DNA修复中作用机制的研究

项目编号： No.31471226

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 遗传学与生物信息学、细胞生物学

项目作者： 汪香婷

作者单位： 中国科学技术大学

项目金额： 85万元

中文摘要： 长链非编码RNA（lncRNA）是长度大于200个碱基的非编码RNA，在细胞生命活动中起着关键作用，但在DNA修复中的作用不详。申请人发现lncRNA结合蛋白TLS在DNA损伤后迅速发生泛素化调节，具有引导γH2AX修复焦点的形成和促进DNA同源重组（HR）修复的作用。TLS此项功能依赖于RNA，但作用的RNA不详。本项目拟首先发掘γ射线照射后与TLS结合的lncRNA，然后以TLS介导的DNA修复通路为主线，着重研究对HR修复有促进作用的lncRNA，深入探讨这些lncRNA与TLS的相互作用对二者功能的影响，并初步探索这些lncRNA在肿瘤细胞增殖和对射线敏感性中的作用。本项目旨在发现促进HR修复并影响肿瘤细胞生长和射线敏感性的lncRNA，阐明其作用机制。该研究将丰富对lncRNA调控网络在DNA损伤应答反应中的认识，为新型肿瘤增敏药物的研发提供理论基础和药物靶点。

中文关键词： 长链非编码RNA；DNA损伤与修复；RNA-蛋白相互作用；肿瘤表观遗传

英文摘要： Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides that play key roles in cellular function.However, the roles of lncRNAs in DNA repair is largely unknown. We found that lncRNA-binding protein TLS is rapidly ubiquitinated under genotoxic stress and plays critical roles in promoting DNA homologues recombination (HR) repair and γH2AX foci formation in an RNA-dependent manner. The involved RNA is not yet discovered. This proposal will first identify the lncRNAs that are capable of binding to TLS under γ-irradiation treatment. Next, we will focus on investigating the roles of those HR repair promoting lncRNAs, and exploring the importance of lncRNA-TLS interaction in their function application. Moreover, we will investigate the roles of these lncRNAs in cancer cell proliferation and γ-irradiation sensitivity. We expect to discover the functional lncRNAs in regulating HR repair, cancer cell growth and irradiation response,as well as the underlying mechanism. This work will help to expand our current knowledge on the roles of lncRNAs in DNA damage response,and to provide fundamental knowledge and new targets for tumor sensitizing drug study.

英文关键词： long non-coding RNA;DNA damage repair;RNA-protein interaction;cancer epigenetics