去泛素化酶在调控DNA损伤应答和基因组稳定性中的作用机制及其与肿瘤的关系

DNA damage induced by numerous internal and environmental hazards triggers genomic instability, and ultimately promotes tumorigenesis. To cope with these damages, cells have developed a DNA damage response (DDR) system to sense and repair DNA lesions. Various protein modifications play important roles during DNA damage response. Among them, the fine-tuning regulations of the ubiquitination and deubiquitination of the key proteins in DDR play critical roles in the early response to the damage and also the termination of repair. Therefore, deubiquitinases are become new therapeutic options in cancer therapy. To identify more deubiquitinases involved in DDR and elucidate their mechanisms and correlation with the tolerance to drug and radiation treatments are of great importance. Our previous study has found some deubiquitin enzymes and factors that can deubiquitinate H2A and PCNA in response to DNA damage. In this study, we will systematiclly investigate the functions and underlying mechanisms of these regulators in DNA damage response, to understand the effects of deubiquitination on the modifications of histone proteins, the chromatin structure, the recruitment of DNA damage repair proteins, and the genomic stability. Moreover, we will also elucidate the effects of depleted-deubiquitinases on tumor cells growth, mutations, sensitivity to chemotherapy and radiotherapy, and tumorigenesis. These studies will help us to further understand the molecular mecahnisms of tumorigenesis and drug resistance, and provide useful information for increasing the radiation and chemotherapy sensitivity and improving the prognosis of tumor patients, and also provide insight for finding novel targets in tumor diagnosis and treatment in the future.

DNA损伤会造成基因组的不稳定，导致肿瘤等恶性疾病的发生。泛素化等翻译后修饰在DNA损伤应答（DDR）调节中发挥重要作用，DDR中关键蛋白的泛素化和去泛素化修饰的精细调控，对于在损伤初期细胞有效应答和在修复完成后及时地终止修复至关重要，去泛素化酶也因而成为肿瘤治疗的潜在靶标。针对DDR中去泛素化酶对组蛋白等的调控作用机制及其对放化疗敏感性的影响开展深入研究具有重要生物学意义。我们的前期工作发现了一些DDR关键蛋白H2A等的去泛素化酶。在此基础上，本课题将深入研究这些去泛素化酶是如何通过调控组蛋白的修饰以及染色质结构影响基因组的稳定性，揭示其在DDR中发挥作用的分子机制；同时，探讨其表达异常或酶活性缺失对肿瘤细胞生存、突变、放化疗敏感性以及成瘤的影响,明确其与肿瘤发生发展和耐药的关系。这些研究有助于揭示肿瘤细胞放化疗耐受的形成机制，为增加放化疗敏感性并显著改善肿瘤病人的预后提供有用信息。

DNA损伤会造成基因组的不稳定，导致肿瘤等恶性疾病的发生。泛素化等翻译后修饰在DNA损伤应答（DDR）中发挥重要作用，DDR中关键蛋白的不同翻译后修饰的精细调控对于高效的损伤修复至关重要。本项目围绕DNA双链断裂和跨损伤合成这两个损伤修复通路，鉴定在DDR中发挥作用的去泛素化酶等调控因子，阐明这些调控因子调节DDR和基因组稳定性的作用和机制，探讨其功能的异常在肿瘤细胞生存、化放疗中的作用，揭示它们与肿瘤发生发展和耐药的关系。本项目的研究发现去泛素化酶OTUD6A、A20、USP38与USP1协同作用的氧化还原感应器HSCARG，以及hCINAP等通过调节H2A及关键损伤修复蛋白TopBP1、RNF168、HDAC1、PCNA的泛素化和类泛素化修饰，影响修复蛋白的招募与解离，在DNA损伤应答和基因组稳定性维持中发挥重要调控作用，并且证明这些调控因子功能的失活会分别影响乳腺癌、肾癌、结直肠癌和白血病AML以及APL的发生发展。该研究有助于揭示肿瘤细胞放化疗耐受的形成机制，为增加放化疗敏感性并显著改善肿瘤病人的预后提供有用信息。