组蛋白修饰H3K36me3调控肿瘤细胞DNA损伤信号通路机制的研究

项目名称： 组蛋白修饰H3K36me3调控肿瘤细胞DNA损伤信号通路机制的研究

项目编号： No.81472628

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： 李枫

作者单位： 武汉大学

项目金额： 85万元

中文摘要： 人类组蛋白H3K36位点的三重甲基化 (H3K36me3)是一个重要的表观遗传修饰，在多个不同的癌症组织中发现其缺失或者水平降低，暗示该修饰很可能与肿瘤致病机制有着密切的关系。我们之前研究发现H3K36me3在复制的早期与DNA错配修复关键蛋白MutSα相互作用从而调控DNA修复并维持了基因组稳定性，在此基础上进一步预实验发现敲除H3K36me3的HeLa细胞或缺失H3K36me3的其它肿瘤细胞在DNA损伤试剂处理时敏感性降低，无法激活关键信号通路蛋白ATR，更为重要的是其细胞周期不能被阻遏到G2/M期以及细胞凋亡减少。本研究拟证明肿瘤细胞缺失组蛋白修饰H3K36me3会导致DNA损伤信号通路异常并影响相关的细胞周期和细胞凋亡，不仅能进一步揭示了H3K36me3在肿瘤致病机制中的意义，也为个体化治疗和DNA损伤类肿瘤药物的应用提供新的依据。

中文关键词： C25_其它肿瘤；表观遗传修饰；DNA；损伤；DNA修复；信号通路

英文摘要： The human histone mark H3K36me3 is one of the key epigenetic modifications that depleted or significantly decreased in multiple tumor tissues, implying its role in tumorigenesis. Our previous study revealed that H3K36me3 interact with DNA mismatch repair key protein MutSα in the early S phase and thus regulate the DNA repair and maintain the genome stability. Our further progress showed that depletion of H3K36me3 in tumor cells render it became more resistent to DNA damage reagent,failed to activate the key DNA damage signaling pathway protein ATR，as well as unable to be arrested at G2/M phase and exhibit less cell apoptosis in the absence of H3K36me3.The maojor purpose of this study is to prove that H3K36me3 depleted tumor cells lead to abnormal DNA signaling pathway and influence the related cell cycle and cell apoptosis. Our findings not only shed light on the role of H3K36me3 in the cancer predisposition, but also provide novel clues for the personalized treatment and the application of DNA-damaging anti-cancer drugs.

英文关键词： Tumor;Epigenetic modification;DNA damage;DNA repair;Signaling pathway