RBX1介导TRF1泛素化修饰维持端粒稳定性拮抗紫外线所致皮肤光老化的机制研究

预防长波紫外线（UVA）诱导的皮肤端粒DNA损伤和光老化是关乎人民健康的重要科学问题。TRF1作为重要的端粒结合蛋白，在细胞完成有丝分裂后从端粒脱离并发生泛素化降解。但TRF1在特定细胞周期（G1期）限制蛋白水平的机制，及对维持端粒稳态的意义尚未阐明。前期工作发现，RBX1在G1期细胞上调后，促进TRF1泛素化修饰，并拮抗UVA所致端粒缩短和细胞衰老。本课题将深入研究RBX1调控TRF1泛素化修饰对端粒和染色体稳定性的影响：1）明确RBX1对不同细胞周期TRF1泛素化降解的影响规律；2）探索RBX1调控TRF1泛素化修饰对UVA所致端粒损伤的拮抗作用，尤其对端粒缺失和端粒长度的影响；3）体内和体外实验相结合，分析RBX1介导TRF1泛素化修饰对UVA所致细胞衰老和小鼠皮肤光老化的影响。本项目将加深对TRF1蛋白对端粒调控机制的理论认知，并为延缓UVA所致皮肤衰老和降低癌症风险寻找防治策略。

How to prevent long wavelength ultraviolet (UVA) induced skin telomere DNA damage and skin photoaging is critical for human health. Telomeric DNA-binding protein TRF1, is recruited with telomere to cover telomere ends and dissociated from telomere after cell mitosis phase. However, the mechanism about TRF1 limits protein content during G1 phase as telomere uncombined form, and how to exert beneficial effects on telomere stability has not yet been elucidated. Previous studies have found that RBX1 increased in G1 phase and promoted ubiquitin degradation of TRF1, which exerts positive effects on telomere shortening and cell senescence induced by UVA. The present study focuses on ubiquitin degradation of TRF1 mediated by RBX1, and its downstream function: 1) RBX1 regulates ubiquitin degradation of TRF1 in cell cycle-dependent manner; 2) RBX1 protects telomere DNA against UVA-induced DNA damage, especially the combination between TRF1 and telomere DNA and telomere loss; 3) RBX1 protects against skin photoaging exposed with UVA in vivo and in vitro. The project would deepen the understanding of TRF1 telomere protection mechanism, and look for protective strategies for skin aging and cancer risk caused by UVA.