Targeting Rev1-mediated Translesion Synthesis for Cancer Therapy

 描述（由申请人提供）：转录合成是一种基本的细胞防御机制，它使DNA能够在病变部位复制，以促进细胞存活，但代价是复制保真度。这样的过程直接有助于癌细胞存活和化疗后癌症耐药性的发展。真核生物Y家族聚合酶Rev 1是跨损伤合成中必不可少的支架蛋白，其C-末端结构域（CTD）与跨损伤聚合酶rev、rev、rev和rev相互作用，是其功能所必需的。最近的生物化学和结构研究揭示了Rev 1 CTD介导的translesion聚合酶复合物组装的分子基础，并且使用小鼠癌症模型的体内研究已经建立了Rev 1介导的translesion合成作为治疗耐药肿瘤的有希望的新靶点。该提案的目标是开发Rev 1 CTD的小分子拮抗剂作为新型辅助癌症治疗剂，以增强DNA损伤剂对耐药癌症的有效性。这将通过发现、优化和表征破坏Rev 1 CTD在translesion合成中的基本支架功能的先导化合物，并通过证明其使耐药癌症对DNA损伤化疗药物（如顺铂）敏感的能力来实现。

 DESCRIPTION (provided by applicant):Translesion synthesis is a fundamental cellular defense mechanism that enables DNA replication across lesion sites in order to promote cell survival at the cost of replication fidelity. Such a process directly contributes to cancer cell survival and the development of cancer drug resistance after chemotherapy. The eukaryotic Y-family polymerase Rev1 is an essential scaffolding protein in translesion synthesis, and its C-terminal domain (CTD), which interacts with translesion polymerases , ,  and , is absoltely required for function. Recent biochemical and structural investigations have revealed the molecular basis of the Rev1 CTD-mediated assembly of translesion polymerase complexes, and in vivo studies using murine cancer models have established Rev1-mediated translesion synthesis as a promising new target for treatment of drug-resistant tumors. The goal of this proposal is to develop small molecule antagonists of the Rev1 CTD as novel adjuvant cancer therapeutics to enhance the effectiveness of DNA-damaging agents against drug-resistant cancers. This will be achieved by discovery, optimization, and characterization of lead compounds that disrupt the essential scaffolding function of the Rev1 CTD in translesion synthesis and by demonstrating their ability to sensitize drug-resistant cancers to DNA-damaging chemotherapeutics, such as cisplatin.