去乙酰化酶SIRT2调控SMC1及其对基因组稳定性的影响机制研究

SMC1 (Structural maintenance of chromosome protein 1) mediated chromosome structure stability/cell cycle arrest that is considered as an important mechanism for the maintenance of genome integrity. Histone deacetylase SIRT2 is a new type tumor suppressor gene, which has a close association with tumorigenesis. Our recent work has shown that SIRT2 interacts and deacetylates SMC1, modulating its phosphorylation, suggesting that SIRT2 may play an important role in the cell cycle progression and genome stability through regulating the deacetylation and phosphorylation of SMC1. This research project will continue to study the mechanism of the regulation between SIRT2 and SMC1 on genome integrity and tumor formation. During this study, we will explore the site of acetylation and function of SMC1 using molecular biology, bioinformatics and biochemistry methods. We will also investigate the effects of SIRT2 regulating SMC1 on genome stability and tumor cell growth and proliferation by cell proliferation assay in vitro and nude mice tumor graft methods in vivo. Our research might further elucidate the molecular mechanism of SIRT2 in regulating of genome integrity and tumor inhibition, revealing the functional role of modified form of SMC1 in genome stability and tumor formation, and to explore new cancer drug targets, and treatment programs designed to provide a reasonable basis.

染色体结构维持蛋白SMC1所调控的染色体结构稳定/细胞周期阻滞，是维护基因组稳定的重要途径。去乙酰化酶SIRT2是新近发现的一个重要肿瘤抑制基因，与肿瘤的发生密切相关。我们的近期工作显示，SIRT2通过与SMC1结合调控SMC1乙酰化水平，进而影响其磷酸化水平，提示SIRT2可能通过改变SMC1乙酰化和磷酸化水平，调控细胞周期，影响基因组稳定。本研究项目将深入探索SIRT2对SMC1的调控机制，及其对基因组稳定性和肿瘤形成的影响。我们将通过分子生物学和生物信息学结合生物化学等方法深入解析SIRT2调控SMC1去乙酰化修饰的位点及功能，进而通过细胞体外增殖实验及裸鼠体内成瘤模型研究SIRT2对SMC1调控在肿瘤生长和增殖方面的影响。本研究将阐明SIRT2影响基因组稳定性和抑制肿瘤的分子机制，揭示SMC1修饰形式对基因组稳定性和肿瘤形成的影响，为探索新的药物靶点及设计合理的治疗方案提供依据。

染色体结构维持蛋白SMC1所调控的染色体结构稳定/细胞周期阻滞，是维护基因组稳定的重要途径。去乙酰化酶SIRT2是新近发现的一个重要肿瘤抑制基因，与肿瘤的发生密切相关。本研究项目深入探索SIRT2对SMC1的调控机制，及其对有丝分裂期和肿瘤发生发展的影响。我们的近期工作显示，SIRT2去乙酰化SMC1的K579位点，从而促进了其磷酸化的发生；压力刺激下，SMC1-K579的乙酰化抑制有丝分裂检验点SMC1磷酸化的发生，引起细胞多级行为；无论是在早期结肠癌还是进程性结肠癌标本中，SMC1-K579乙酰化和SMC1磷酸化都呈负相关。重要的是高水平的SMC1-K579乙酰化预后差，而低水平的SIRT2和SMC1磷酸化预后差；瞬时提高SMC1-K579乙酰化水平（模拟乙酰化激活型）导致有丝分裂灾难性死亡，行为抑制肿瘤的生长。我们将通过分子生物学和生物信息学结合生物化学等方法深入解析SIRT2调控SMC1去乙酰化修饰的位点及功能，进而通过细胞体外增殖实验及裸鼠体内成瘤模型研究SMC1-K579乙酰化在肿瘤生长和增殖方面的影响。本研究将阐明SIRT2作为有丝分裂检验点调控SMC1活性和抑制肿瘤的分子机制，揭示SMC1的K579位点有望成为结肠癌治疗的新的药物靶点。