SUMO modification and DNA damage response in cancer therapy

描述(由申请人提供)：小泛素样修饰物(SUMO)家族蛋白的翻译后修饰已被确定为细胞对广泛的DNA损伤试剂和辐射反应的关键事件。放射和化疗都会导致DNA损伤，从而导致基因组不稳定和/或细胞死亡，从而杀死癌细胞。因此，依赖于糖基化的DNA修复机制在癌细胞对这些治疗的耐药性中起着至关重要的作用。然而，SUMO化在DNA损伤反应中的作用机制尚不清楚。我们假设相扑异构体特异性受体蛋白在DNA损伤修复中介导相扑异构体特异性功能。这些研究是基于我们的初步研究，这些研究表明，抑制相扑依赖的蛋白质-蛋白质相互作用抑制了DNA双链断裂的修复，并增加了肿瘤细胞对导致DNA损伤的放射和化疗药物的敏感性。这项研究结合了几种科学上不同但高度协同的方法，包括结构和分子生物学方法，以研究SUMO化在DNA双链断裂修复中的作用，并阐明不同相扑异构体在这些过程中的功能。这些研究还将探讨相扑亚型特异性识别的结构基础，这将为设计相扑亚型特异性功能的抑制剂提供信息。拟议的研究解决了一个创新的概念，并可能导致建立一种新的针对相扑依赖机制的癌症治疗范例。公共卫生评论：这项提案的总体目标是研究SUMO化在DNA损伤反应中的作用。

DESCRIPTION (provided by applicant): Post-translational modifications by the Small Ubiquitin-like Modifier (SUMO) family of proteins have been established as critical events in the cellular response to a wide range of DNA damaging reagents and radiation. Both radiation and chemotherapy kill cancer cells by inducing DNA damage that leads to genomic instability and/or cell death. Therefore, DNA repair mechanisms, which are SUMOylation dependent, play a critical role in the resistance of cancer cells to these treatments. However, the mechanism of SUMOylation in DNA damage response is poorly understood. We hypothesize that SUMO isoform-specific receptor proteins mediate SUMO isoform-specific functions in the repair of DNA damage. The proposed studies are based on our Preliminary Studies, which show that inhibition of SUMO-dependent protein-protein interactions inhibited the repair of DNA double-strand breaks, and increased the sensitivity of tumor cells to radiation and chemotherapeutic drugs that induce DNA damage. The proposed research integrates several scientifically diverse but highly synergistic approaches, including structural and molecular biological methods, to investigate the role of SUMOylation in the repair of DNA double-strand breaks, and to elucidate the functions of different SUMO isoforms in these processes. These studies will also investigate the structural basis for SUMO isoform-specific recognition, which will provide information for designing inhibitors of SUMO isoform-specific functions. The proposed studies address an innovative concept, and could lead to the establishment of a new paradigm of targeting SUMO-dependent mechanisms for cancer therapy. PUBLIC HEALTH REVELANCE: The overall goal of this proposal is to investigate the role of SUMOylation in DNA damage response.