Ufm1对p53的共价修饰在干细胞稳态调控中的作用及机制研究

As the gatekeeper of genome stability and cellular homeostasis, p53 plays a critical role in the regulation of cellular senescence, stem cell exhaustion and aging. In general, p53 function depends on its precise post-translational modifications and interactions between different modifications. Although some evidences showed that the phosphorylation or acetylation of p53 regulate p53 functions in response to senescence stresses, however, the detailed mechanisms of regulation of p53 activity on aging is still unclear. Our preliminary study found that p53 can be modified by ubiquitin fold modifier 1(Ufm1), which is a novel protein modification of p53. Such modification affects the stability of p53 and its response to DNA damage stress, suggesting that Ufm1 modification involved in activation of p53. To explore the biological function of p53 ufmylation, we will investigate the signal pathways involved in modification and regulation of p53 ufmylation, and the function of p53 ufmylation in stem cell aging, especially maintenance of mesenchymal stem cell homeostasis. Our proposed study would shed new light on the mechanisms of p53 regulations and its function in stem cell aging.

p53是细胞内的核心调控因子，参与衰老压力应答，与干细胞耗竭息息相关。p53功能调控依赖于其多种蛋白翻译后修饰协同作用。虽有证据表明p53不同位点的磷酸化或乙酰化修饰参与衰老过程，但是p53通过蛋白修饰调控参与衰老调控的机制仍不清晰。本项目前期结果发现p53具有新的蛋白修饰形式—Ufm1共价修饰（Ufmylation），并发现此种修饰影响p53的稳定性及对DNA损伤应答，提示Ufmylation修饰参与p53的活性调节甚至衰老过程。为了探索p53的Ufmylation修饰的生物学功能及对衰老的影响，本项目拟采用分子生物学、细胞生物学及系统生物学技术，研究Ufmylation修饰p53的机理、被调控通路，及Ufmylation修饰对p53的功能影响，并阐明在干细胞衰老尤其是间充质干细胞稳态维持中的调控作用及机制，为p53的功能研究及对干细胞衰老机制研究提供新的思路及证据。

p53是细胞内的关键调控因子，参与细胞对于多种压力刺激的应答，具有广泛的生物学功能。p53的翻译后修饰决定了p53的功能调控。本项目发现p53具有新的蛋白修饰形式-Ufmylation修饰，在后续研究中，本项目发现UFM1主要通过第351、357、370、373位赖氨酸位点修饰p53，修饰过程需要关键蛋白UBA5、UFC1、UFL1、UFM1、DDRGK1的参与, 被Ufm1修饰后的p53能够拮抗其泛素化修饰，增加p53的稳定性，并参与对DNA损伤应激的调控。无论在细胞水平还是临床样本水平，p53的Ufmylation修饰能够增加p53的肿瘤抑制功能。本研究证明ufmylation修饰是p53功能调控的关键修饰，为临床以p53的ufmylation修饰为靶点干预特定肿瘤提供理论依据。