Lei Ming
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Curr Cancer Drug Targets. 2005 Aug;5(5):365-80. doi: 10.2174/1568009054629654.
The MCM complex controls the once per cell cycle DNA replication in eukaryotic cells. In a process known as DNA replication licensing, it primes chromatin for DNA replication by binding origins of DNA replication during the late M to early G1 phase of the cell cycle. Activated by S phase promoting protein kinases, the origin-bound MCM complexes unwind the double stranded DNA at the origins, recruit DNA polymerases and initiate DNA synthesis. Coupled with the initiation of DNA replication in the S phase, the MCM complexes move away from replication origins as a component of the DNA replication fork, likely serving as DNA helicases. Their departure deprives replication origins the ability to re-initiate DNA replication for the reminder of the cell cycle. Because of its vital role in genome duplication in proliferating cells, deregulation of the MCM function results in chromosomal defects that may contribute to tumorigenesis. The MCM proteins are highly expressed in malignant human cancers cells and pre-cancerous cells undergoing malignant transformation. They are not expressed in differentiated somatic cells that have been withdrawn from the cell cycle. Therefore, these proteins are ideal diagnostic markers for cancer and promising targets for anti-cancer drug development. In this article, I will overview the structures and functions of the MCM complex with an effort to integrate insights from recent biochemical and structural studies. Discussions will also cover activities and structures of the complex that may be useful for the development of drug screens.
MCM复合物控制真核细胞中每个细胞周期一次的DNA复制。在一个被称为DNA复制许可的过程中，它在细胞周期的M期末期到G1期早期通过结合DNA复制起点使染色质为DNA复制做好准备。被S期促进蛋白激酶激活后，结合在起点的MCM复合物解开起点处的双链DNA，招募DNA聚合酶并启动DNA合成。伴随着S期DNA复制的起始，MCM复合物作为DNA复制叉的一个组成部分从复制起点处离开，可能充当DNA解旋酶。它们的离开使复制起点在细胞周期的剩余时间内失去重新启动DNA复制的能力。由于其在增殖细胞基因组复制中的关键作用，MCM功能失调会导致染色体缺陷，这可能有助于肿瘤发生。MCM蛋白在恶性人类癌细胞和正在经历恶性转化的癌前细胞中高度表达。它们在已退出细胞周期的分化体细胞中不表达。因此，这些蛋白是理想的癌症诊断标志物和抗癌药物开发的有前景的靶点。在本文中，我将概述MCM复合物的结构和功能，努力整合来自最近生化和结构研究的见解。讨论还将涵盖该复合物可能对药物筛选开发有用的活性和结构。
