Simon Nicholas E, Schwacha Anthony
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Biomed Res Int. 2014;2014:549719. doi: 10.1155/2014/549719. Epub 2014 Aug 28.
Numerous eukaryotic replication factors have served as chemotherapeutic targets. One replication factor that has largely escaped drug development is the Mcm2-7 replicative helicase. This heterohexameric complex forms the licensing system that assembles the replication machinery at origins during initiation, as well as the catalytic core of the CMG (Cdc45-Mcm2-7-GINS) helicase that unwinds DNA during elongation. Emerging evidence suggests that Mcm2-7 is also part of the replication checkpoint, a quality control system that monitors and responds to DNA damage. As the only replication factor required for both licensing and DNA unwinding, Mcm2-7 is a major cellular regulatory target with likely cancer relevance. Mutations in at least one of the six MCM genes are particularly prevalent in squamous cell carcinomas of the lung, head and neck, and prostrate, and MCM mutations have been shown to cause cancer in mouse models. Moreover various cellular regulatory proteins, including the Rb tumor suppressor family members, bind Mcm2-7 and inhibit its activity. As a preliminary step toward drug development, several small molecule inhibitors that target Mcm2-7 have been recently discovered. Both its structural complexity and essential role at the interface between DNA replication and its regulation make Mcm2-7 a potential chemotherapeutic target.
许多真核生物复制因子已成为化疗靶点。一个在很大程度上未被用于药物研发的复制因子是Mcm2 - 7解旋酶。这种异源六聚体复合物形成了许可系统，在起始阶段在复制起点组装复制机器，也是在延伸过程中解开DNA的CMG（Cdc45 - Mcm2 - 7 - GINS）解旋酶的催化核心。新出现的证据表明，Mcm2 - 7也是复制检查点的一部分，复制检查点是一个监测和应对DNA损伤的质量控制系统。作为许可和DNA解旋所需的唯一复制因子，Mcm2 - 7是一个主要的细胞调节靶点，可能与癌症相关。六个MCM基因中至少有一个发生突变在肺癌、头颈癌和前列腺鳞状细胞癌中尤为普遍，并且在小鼠模型中已表明MCM突变会导致癌症。此外，包括Rb肿瘤抑制家族成员在内的各种细胞调节蛋白会结合Mcm2 - 7并抑制其活性。作为药物研发的初步步骤，最近发现了几种靶向Mcm2 - 7的小分子抑制剂。Mcm2 - 7的结构复杂性及其在DNA复制与其调节之间界面的关键作用，使其成为一个潜在的化疗靶点。
