mTOR信号通路对DNA双链断裂损伤修复的调控机制研究

DNA double-strand breaks (DSBs) is one of the most serious forms of DNA damage, which, if unrepaired, results cell death and gene mutations. Dysfunction of the DSBs repairing system in cells leads to genomic instability, a hallmark of almost all human cancers. The mammalian target of rapamycin (mTOR) controls cell growth, cell proliferation, cell survival, senecense and metabolism by integrating genotoxic stresses and different extracellular stresses including those related to nutrients, energy and oxygen level. DNA damaging reagents, irradiations and chemical inhibitors of mTOR pathway are wildly used in cancer therapeutics, in this study the mechanisms of how mTOR signaling regulate DSBs repairing will be investigated. we will exploit the functional interplay between mTOR pathway and DSBs repairing signaling by utilizing molecular and biochemical methods both in vitro and in vivo. The success of this project could eventually help us to understand the mechanism of drug resistances and further to design new therapeutic intervention targets.

DNA双链断裂损伤是威胁细胞生存、导致基因突变的重要因素，其修复机制紊乱导致的细胞基因组不稳定性是癌症主要特征之一。哺乳动物雷帕霉素靶蛋白（mTOR）信号通路通过感受细胞外环境包括营养、能量、氧气和基因毒等各种压力来调节细胞的生长、增殖、凋亡、衰老和代谢等各种生理功能。由于DNA损伤试剂或离子辐射以及mTOR信号通路抑制剂广泛应用于各类恶性肿瘤的临床治疗，本课题将着重研究mTOR信号通路对DNA双链断裂修复的调控机制，我们应用生化、分子生物学基本技术在细胞和动物及临床样本层面研究两者之间的相互作用，本研究课题的成功实施将为我们理解肿瘤细胞耐药性和发掘新的药物靶点提供理论依据。

能量、营养代谢以及生长因子等环境因素对于细胞基因组稳定性的影响意义重大，但是其具体的作用机制知之甚少。在这个研究中我们发现雷帕霉素靶蛋白复合物一（mTORC1）及其下游核糖体激酶S6K这一细胞生长信号枢纽能通过作用于DNA双链损伤修复E3连接酶RNF168来调控DNA损伤应答，影响基因组的稳定性。具体而言，LKB1、TSC1/2等抑癌基因的失活高度活化mTORC1-S6K，后者通过磷酸化RNF168 60位丝氨酸使之失活并促进其蛋白酶体降解，使得DNA损伤修复受到抑制，导致基因组不稳定从而影响细胞的恶性转化。这些研究结果揭示了mTORC1-S6K信号通路在DNA损伤应答中的重要作用，也表明能量、营养以及生长激素等环境因素能对高等生物基因组稳定性具有重要影响。