SUMO modification and DNA damage response in cancer therapy

描述（由申请人提供）：已确定小泛素样修饰物（SUMO）蛋白家族的翻译后修饰是细胞对各种DNA损伤试剂和辐射反应的关键事件。放疗和化疗都是通过诱导DNA损伤来杀死癌细胞，导致基因组不稳定和/或细胞死亡。因此，依赖SUMO化的DNA修复机制在癌细胞对这些治疗的抗性中起着关键作用。然而，SUMO化在DNA损伤反应中的机制知之甚少。我们推测，SUMO亚型特异性受体蛋白介导的SUMO亚型特异性功能的DNA损伤的修复。我们的初步研究表明，抑制SUMO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诱导DNA损伤的放射和化疗药物的敏感性。这项研究整合了几种科学上多样化但高度协同的方法，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SUMO亚型在这些过程中的功能。这些研究还将探讨SUMO异构体特异性识别的结构基础，这将为设计SUMO异构体特异性功能的抑制剂提供信息。拟议的研究提出了一个创新的概念，并可能导致建立一个新的范式，靶向SUMO依赖性机制的癌症治疗。公共卫生宣传：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.