The Mcm2-7 replicative helicase: a promising chemotherapeutic target.
The Mcm2-7 replicative helicase: a promising chemotherapeutic target.
复制标题
MCM2-7复制解旋酶：一个有希望的化学治疗靶标。
DOI：
10.1155/2014/549719
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发表时间：
2014
影响因子：
--
通讯作者：
Schwacha A
中科院分区：
文献类型：
--
作者：
Simon NE;Schwacha A
许多真核生物复制因子已作为化疗靶点。一种在很大程度上逃脱了药物开发的复制因子是Mcm 2 -7复制解旋酶。这种异源六聚体复合物形成许可系统，该许可系统在起始期间在起点组装复制机器，以及在延伸期间解旋DNA的CMG（Cdc 45-Mcm 2 -7-GINS）解旋酶的催化核心。新出现的证据表明，Mcm 2 -7也是复制检查点的一部分，复制检查点是一种质量控制系统，可以监测和响应DNA损伤。作为许可和DNA解旋所需的唯一复制因子，Mcm 2 -7是可能与癌症相关的主要细胞调节靶点。六个MCM基因中的至少一个中的突变在肺、头颈部和前列腺的鳞状细胞癌中特别普遍，并且MCM突变已被证明在小鼠模型中引起癌症。此外，各种细胞调节蛋白，包括Rb肿瘤抑制因子家族成员，结合Mcm 2 -7并抑制其活性。作为药物开发的初步步骤，最近发现了几种靶向Mcm 2 -7的小分子抑制剂。Mcm 2 -7的结构复杂性和在DNA复制及其调控之间的界面上的重要作用使其成为潜在的化疗靶点。
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.