组蛋白去乙酰化酶SirT7翻译后修饰及其在调控肿瘤耐药中的作用研究

化疗耐药是肿瘤治疗的瓶颈，而DNA损伤修复是肿瘤细胞耐药性的重要原因之一，因此深入研究DNA损伤修复的调控机制是解决肿瘤耐药的分子基础。错配修复（MMR）系统参与肿瘤细胞中DNA损伤诱导下的细胞凋亡，其功能缺失（dMMR）代表肿瘤微卫星不稳定性（MSI），预示肿瘤耐药，然而其调控机制尚不清楚。组蛋白去乙酰化酶SirT7参与肿瘤能量限制调控、DNA损伤修复，是否作为肿瘤耐药的调节因子还有待研究。我们发现SirT7在化疗药物刺激下发生磷酸化修饰并且定位改变，进一步与MMR系统中的蛋白MSH2结合并使其去乙酰化，进而抑制MMR功能，诱导MSI的发生，最终导致肿瘤耐药。我们拟研究SirT7的磷酸化在肿瘤耐药中的调控作用，为肿瘤耐药检测提供新指标；建立肿瘤细胞中SirT7与dMMR/MSI的相关性，为肿瘤治疗提供新靶点、新策略。

Tumor chemoresistance is a key challenge that oncology seeks to understand and overcome. One of the important reasons of chemoresistance is the DNA damage repair, therefore, it is necessary to further study on the mechanism for regulating DNA damage repair in cancer cells. DNA mismatch (MMR) system plays a critical role in initiation of apoptosis and MMR deficiency (dMMR) predisposes to microsatellite instability (MSI) in tumors and chemoresistance. However, the molecular regulatory mechanism of dMMR/MSI in cancer cells remains incompletely understood. Histone deacetylase SirT7 has been showed function as a stress sensor in response to glucose starvation condition and DNA damage. Whether and how SirT7 is dynamically regulated in chemoresistance are largely unexplored. In order to identify the relationship of SirT7 and tumor chemoresistance, we propose a new mechanism for the role of SirT7 in tumor resistance upon DNA damage response, in which SirT7 is phosphorylated, causing a redistribution of SirT7 from nucleolus to nucleoplasm. After that, SirT7 in nucleoplasm deacetylates MSH2 and negatively regulates MMR, and thus resulting in MSI and resistance of DNA damage stress. There will be two important consequences in our study: we will reveal that SirT7 can serves as a potential maker for tumor chemoresistance through elucidating the molecular mechanism and function of phosphorylation of SirT7 in tumor chemoresistance; and the negative correlation between Sirt7 and dMMR/MSI in cancer cells will be established，leading to a new diagnosis, prognosis and treatment of tumors.