Sirtuins（SirT1至SirT7）是一类与衰老、癌症和代谢紊乱疾病相关的去乙酰化酶。申请人前期报道SirT1参与肿瘤耐药，发现SirT1的修饰和降解机制及其如何调控自噬及自噬依赖的肝脏脂肪代谢。与其它Sirtuin不同，SirT7主要在核仁分布。近期发现SirT7与肿瘤和脂代谢紊乱相关。但SirT7底物蛋白发现非常有限、其酶活性调控及降解研究几乎为空白。申请人发现：多种外界压力可诱发SirT7磷酸化和细胞亚定位变化；SirT7磷酸化可调控其定位和降解，SirT7的rDNA转录活性和降解受REGγ蛋白酶体调控，REGγ缺失可诱发能量依赖的肿瘤饿死现象；SirT7可与一些DNA损伤和死亡调控蛋白结合。本课题拟研究SirT7磷酸化和降解机制，阐释REGγ-SirT7相互作用如何调控细胞能量稳态和肿瘤饿死，并探讨SirT7如何与新结合蛋白作用并调控细胞应激，为肿瘤治疗提供新理论和新思路。

The Sirtuins (SirT1 to SirT7) are a family of protein deacetylase that closely linked to aging, tumor and metabolism disorder diseases. We have previously reported a role for SirT1 in cancer drug resistance, and revealed signaling pathways regulating SirT1 phosphorylation and degradation and their roles in mediating autophagy and autophagy-dependent lipid degradation in liver. SirT7, the only deacetylase found to be localized in the nucleous, is less studied. In recent years SirT7 is found closely related to cancer and lipid metabolism disorders. Howerver SirT7 downstream targets remain largely unknown, and how SirT7 activity and degradation are regulated need to be elucidated. Our primary studies identified that SirT7 can be modified by phosphorylation and its subcellular localization changed markedly under various stress conditions, phosphorylation may regulate SirT7 subcellular distribution and degradation, REGγ proteasome promotes SirT7 degradation, and REGγ deficicency may promote an engery-dependent tumor cell death under starvation, SirT7 may also interact with some new important DNA damage and cell death regulating proteins. In this proposal we plan to study the role of REGγ-SirT7 interaction in regulationg cellular homeostasis and tumor cell death, understanding the regulatory mechanisms and functions of SirT7 phosphorylation and degradation, revealing the functional interplay between SirT7 and its new interacting proteins in regulating cell stress response , with aims to provide clues to new ways to cancer therapy.