Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Rd, Storrs, CT 06029-3092, USA.
Molecules. 2021 Sep 13;26(18):5544. doi: 10.3390/molecules26185544.
Translesion synthesis (TLS) is an error-prone DNA damage tolerance mechanism used by actively replicating cells to copy past DNA lesions and extend the primer strand. TLS ensures that cells continue replication in the presence of damaged DNA bases, albeit at the expense of an increased mutation rate. Recent studies have demonstrated a clear role for TLS in rescuing cancer cells treated with first-line genotoxic agents by allowing them to replicate and survive in the presence of chemotherapy-induced DNA lesions. The importance of TLS in both the initial response to chemotherapy and the long-term development of acquired resistance has allowed it to emerge as an interesting target for small molecule drug discovery. Proper TLS function is a complicated process involving a heteroprotein complex that mediates multiple attachment and switching steps through several protein-protein interactions (PPIs). In this review, we briefly describe the importance of TLS in cancer and provide an in-depth analysis of key TLS PPIs, focusing on key structural features at the PPI interface while also exploring the potential druggability of each key PPI.
跨损伤合成（TLS）是一种易错的 DNA 损伤容忍机制，活跃复制的细胞利用该机制复制 DNA 损伤并延伸引物链。TLS 确保细胞在存在受损 DNA 碱基的情况下继续复制，尽管这会增加突变率。最近的研究表明，TLS 在挽救接受一线致基因突变药物治疗的癌细胞方面发挥了明确作用，使它们能够在化疗诱导的 DNA 损伤存在的情况下复制和存活。TLS 在化疗初始反应和获得性耐药的长期发展中的重要性使其成为小分子药物发现的一个有趣靶点。正确的 TLS 功能是一个复杂的过程，涉及一个异源蛋白复合物，该复合物通过几个蛋白-蛋白相互作用（PPIs）介导多个附着和切换步骤。在这篇综述中，我们简要描述了 TLS 在癌症中的重要性，并对关键的 TLS PPI 进行了深入分析，重点关注 PPI 界面上的关键结构特征，同时还探讨了每个关键 PPI 的潜在成药性。
