微卫星不稳定性恶性肿瘤合成致死新靶点WRN的研究进展

Research Progress on the Synthetic Lethal New Target WRN in Microsatellite Instability Malignant Tumors

关键词:  WRN  合成致死  微卫星不稳定性恶性肿瘤  WRN抑制剂

Key words:  WRN  synthetic lethal  microsatellite instability malignant tumors  WRN inhibitor

摘要:

微卫星不稳定性（microsatellite instability，MSI）是一种肿瘤细胞中由错配修复受损或缺陷导致而出现新的微卫星等位基因的现象。MSI可以导致肿瘤细胞基因组进一步紊乱和突变，从而促进恶性肿瘤的发生发展，是公认的重要致癌途径之一。Werner syndrome protein （WRN）解旋酶是属于RecQ家族的DNA解旋酶，该酶在DNA修复和维持基因组稳定性中发挥着重要的作用。近年来研究发现，MSI恶性肿瘤的生长高度依赖WRN解旋酶，提示WRN是潜在的MSI恶性肿瘤合成致死新靶点。文章系统综述了WRN解旋酶的结构和生物学功能，总结该蛋白作为合成致死新靶点的最新进展，以及WRN解旋酶抑制剂的研究进展，以期为MSI恶性肿瘤的治疗和WRN抑制剂研发提供参考。

Abstract:

Microsatellite instability(MSI) is a phenomenon in which new microsatellite alleles arise due to impaired or defective DNA mismatch repair in tumor cells. As one of the recognized important oncogenic pathways, MSI can lead to further disorder and mutation of tumor cell genome, thereby promoting the occurrence and development of malignant tumors. Werner syndrome protein (WRN) helicase, belonging to the RecQ family, plays an important role in DNA repair and maintenance of genome stability. Recent studies have discovered that the growth of malignancies with MSI is significantly reliant on WRN helicase, suggesting that targeting WRN could be a promising approach for developing therapies against MSI-associated cancers. Therefore, this review aims to conduct a systematic review of the structure and biological functions of WRN helicase, which is a new target for synthetic lethality. Additionally, latest progress on WRN helicase inhibitors are overviewed with the goal of providing a reference for the treatment of MSI malignant tumors and the development of WRN inhibitors.