TRIM28介导的RCC2蛋白SUMO化修饰调控细胞有丝分裂的机制和功能研究

细胞周期是细胞生命活动的基本过程，其失调可导致基因组不稳定性及肿瘤发生。已有研究表明蛋白质的SUMO修饰广泛参与细胞周期的进程，而许多作用机制尚不明确。 我们前期研究发现染色体凝缩调节因子RCC2可调控有丝分裂的进入与退出，近期又取得新的进展：1) RCC2的K96氨基酸被SUMO1共价修饰；2) SUMO化酶TRIM28和去SUMO化酶SENP3协同调控RCC2蛋白SUMO修饰的动态变化；3) 无SUMO化位点的RCC2(K96R)突变蛋白降低着丝粒间张力，延迟有丝分裂退出；4）RCC2敲除显著增强细胞对紫杉醇敏感性。由此我们提出科学假说：RCC2通过TRIM28介导SUMO化修饰，维持有丝分裂的正常退出。本研究将详尽阐明RCC2调控有丝分裂进入与退出的分子机制，并在细胞、动物水平揭示TRIM28-RCC2通路在乳腺癌中的肿瘤学功能，为乳腺癌的诊断及靶向治疗提供新的理论依据。

Precise regulation of cell cycle plays an important role in the basic function of cell, and disorder of cell cycle leads to oncogenesis. It has been reported that SUMOylation is widely involved in cell cycle transition. However, the detailed mechanism is unclear. Our previous studies found that RCC2, regulator of chromosome condensation 2, is involved in mitotic entry and exit. Recently, new progress has been achieved: 1) the K96 amino acid of RCC2 is covalently modified by SUMO1; 2) SUMO E3 ligase TRIM28 and deSUMO enzyme SENP3 cooperatively regulate the dynamic modification of RCC2 SUMOylation; 3) depletion of RCC2 SUMOylation reduced the tension between kinetochore-microtubule and delayed mitosis exit; 4) functional study indicated that RCC2 depletion rendered cells more sensitive toward paclitaxel in MDA-MB-231. Taken together, we may conclude that TRIM28 mediated RCC2 SUMOylation maintains proper entry and exit of mitosis. In this project, we will clarify the detailed mechanism of RCC2 in modulating mitosis entry and exit, and uncover the oncology significance of TRIM28-RCC2 pathway in vivo and in vitro, and providing novel theoretical basis for individualized targeted therapy in breast cancer.