The MCM complex: its role in DNA replication and implications for cancer therapy.
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 They are not expressed in differentiated somatic cells that have been withdrawn from the cell cycle.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.
Lei
Ming
M
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. mlei@mcw.edu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D016503:Drug Delivery Systems; D042822:Genomic Instability; D006801:Humans; D064111:Minichromosome Maintenance Complex Component 2; D064168:Minichromosome Maintenance Complex Component 7; D009369:Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C084859:MCM2 protein, human; C101624:MCM7 protein, human; D064111:Minichromosome Maintenance Complex Component 2; D064168:Minichromosome Maintenance Complex Component 7