Ishimi Yukio
College of Science, Ibaraki University.
Genes Genet Syst. 2018 Nov 10;93(4):125-133. doi: 10.1266/ggs.18-00026. Epub 2018 Oct 23.
Recently published structural and functional analyses of the CMG complex have provided insight into the mechanism of its DNA helicase function and into the distinct roles of its central six component proteins MCM2-MCM7 (MCM2-7). To activate CMG helicase, the two protein kinases CDK and DDK, as well as MCM10, are required. In addition to the initiation of DNA replication, MCM function must be regulated at the DNA replication steps of elongation and termination. Polyubiquitylation of MCM7 is involved in terminating MCM function. Reinitiation of DNA replication in a single cell cycle, which is prevented mainly by CDK, is understood at the molecular level. MCM2-7 gene expression is regulated during cellular aging and the cell cycle, and the expression depends on oxygen concentration. These regulatory processes have been described recently. Genomic structural alteration, which is an essential element in cancer progression, is mainly generated by disruptions of DNA replication fork structures. A point mutation in MCM4 that disturbs MCM2-7 function results in genomic instability, leading to the generation of cancer cells. In this review, I focus on the following points: 1) function of the MCM2-7 complex, 2) activation of MCM2-7 helicase, 3) regulation of MCM2-7 function, 4) MCM2-7 expression, and 5) the role of MCM mutation in cancer progression.
最近发表的CMG复合物的结构和功能分析，为深入了解其DNA解旋酶功能的机制以及其核心六种组成蛋白MCM2-MCM7（MCM2-7）的不同作用提供了线索。为了激活CMG解旋酶，需要两种蛋白激酶CDK和DDK以及MCM10。除了启动DNA复制外，MCM功能还必须在DNA复制的延伸和终止步骤中受到调控。MCM7的多聚泛素化参与终止MCM功能。在单细胞周期中DNA复制的重新启动主要受到CDK的阻止，这在分子水平上已得到理解。MCM2-7基因表达在细胞衰老和细胞周期过程中受到调控，并且该表达取决于氧浓度。这些调控过程最近已有描述。基因组结构改变是癌症进展中的一个关键因素，主要由DNA复制叉结构的破坏产生。MCM4中的一个点突变会干扰MCM2-7功能，导致基因组不稳定，进而导致癌细胞的产生。在这篇综述中，我重点关注以下几点：1）MCM2-7复合物的功能，2）MCM2-7解旋酶的激活，3）MCM2-7功能的调控，4）MCM2-7的表达，以及5）MCM突变在癌症进展中的作用。
