去泛素化酶OTUD6A通过CDC6介导的细胞增殖调控机制及其致病作用

细胞增殖是机体重要的生命特征，体内有复杂而精确的机制调控周期相关基因的表达以保证增殖的顺利运行。CDC6是一重要的增殖调控蛋白，其异常表达与肿瘤等疾病密切相关。已知E3泛素连接酶介导的泛素化－-蛋白酶体降解途径在CDC6表达调控中扮演着重要的作用，然而对去泛素化在CDC6表达调控中的作用及其机制目前几乎一无所知。我们最新发现去泛素化酶OTUD6A能够与CDC6相互结合并降低CDC6的泛素化水平，提高CDC6的蛋白稳定性，促进其表达；OTUD6A促进细胞增殖，并且该功能依赖于其对CDC6表达的调控作用。这些结果提示OTUD6A可能通过去泛素化CDC6促进其表达，进而影响细胞增殖。为此，本课题拟利用细胞和小鼠模型并结合临床标本验证，分析OTUD6A调控CDC6在细胞增殖及肿瘤中的作用并明确其具体机制，为进一步认识细胞增殖调控的分子机制，筛选新的肿瘤标志物和抗肿瘤靶点提供理论基础。

The precise regulation of cell cycle-associated protein expression is essential for correct cell proliferation, which is an important life feature of organisms. CDC6 is a key cell proliferation regulator, and aberrant expression of CDC6 had been proven to play a vital role in human malignancies. CDC6 expression is tightly regulated during the cell cycle, and E3 ubiquitin ligases mediated CDC6 ubiquitination and degradation is important to ensure proper timing and coordination of cell proliferation. However, the roles and mechanisms of CDC6 deubiquitination in cell cycle remain largely unclear. More recently, we found that deubiquitinase OTUD6A could interact with, and deubiquitinate CDC6, and thus stabilizes CDC6 protein. Moreover, we also demonstrated that OTUD6A promoted cell proliferation through upregulation of CDC6 expression. These findings suggest that OTUD6A is involved in cell proliferation through deubiquitinating and stabilizing CDC6. In the present proposal, we will characterize the role of OTUD6A-CDC6 axis in cell proliferation using cellular and mouse model in vitro and in vivo and further identify the mechanism by which OTUD6A regulates CDC6. In addition, we will also explore the role of OTUD6A in tumorigenesis via deubiquitinating CDC6. This study will advance our understanding of the cell proliferation regulation and help to develop new tumor markers and anticancer targets.