Structure of MCM from archaeal M. Thermoautotrophicum.
The minichromosome maintenance protein complex (MCM) is a DNA helicase essential for genomic DNA replication. Eukaryotic MCM consists of six gene products, MCM2–7, which form a heterohexamer. As a critical protein for cell division, MCM is also the target of various checkpoint pathways, such as the S-phase entry and S-phase arrest checkpoints. Both the loading and activation of MCM helicase are strictly regulated and are coupled to cell growth cycles. Deregulation of MCM function has been linked to genomic instability and a variety of carcinomas.
Function in DNA replication initiation and elongation
MCM2-7 is required for both DNA replication initiation and elongation; its regulation at each stage is a central feature of eukaryotic DNA replication.
During the G1 phase of the cell cycle, Cdc6 and Cdt1 recruit and load MCM2-7 to origins of replication (marked by the binding of Orc1-6) to form a stable and inactive complex called the pre-replication complex (pre-RC).
All six MCM subunits colocalize to origins of replication during pre-RC formation. The inactivation or loss of any of the six MCM subunits during G1 phase blocks pre-RC formation in vivo in yeast and in vitro with Xenopus extracts. The loading of MCM2-7 onto DNA is an active process that requires ATP hydrolysis by both Orc1-6 and Cdc6.
Late G1/early S
In late G1/early S phase, the pre-RC is activated for DNA unwinding by the cyclin-dependent kinases (CDKs) and DDK. This facilitates the loading of additional replication factors (e.g., Cdc45, MCM10, GINS, and DNA polymerases) and unwinding of the DNA at the origin. Once pre-RC formation is complete, Orc1-6 and Cdc6 are no longer required for MCM2-7 retention at the origin, and they are dispensable for subsequent DNA replication.
Upon entry into S phase, the activity of the CDKs and the Dbf4-dependent kinase (DDK) Cdc7 promotes the assembly of replication forks, likely in part by activating MCM2-7 to unwind DNA. Following DNA polymerase loading, bidirectional DNA replication commences.
During S phase, Cdc6 and Cdt1 are degraded or inactivated to block additional pre-RC formation, and bidirectional DNA replication ensues. When the replication fork encounters lesions in the DNA, the S-phase checkpoint response slows or stops fork progression and stabilizes the association of MCM2-7 with the replication fork during DNA repair.
Role in replication licensing
The replication licensing system acts to ensure that the no section of the genome is replicated more than once in a single cell cycle.
The inactivation of any of at least five of the six MCM subunits during S phase quickly blocks ongoing elongation. As a critical mechanism to ensure only a single round of DNA replication, the loading of additional MCM2-7 complexes into pre-RCs is inactivated by redundant means after passage into S phase. 
MCM2-7 activity can also be regulated during elongation. The loss of replication fork integrity, an event precipitated by DNA damage, unusual DNA sequence, or insufficient deoxyribonucleotide precursors, can lead to the formation of DNA double-strand breaks and chromosome rearrangements. Normally, these replication problems trigger an S-phase checkpoint that minimizes genomic damage by blocking further elongation and physically stabilizing protein-DNA associations at the replication fork until the problem is fixed. This stabilization of the replication fork requires the physical interaction of MCM2-7 with Mrc1, Tof1, and Csm3 (M/T/C complex). In the absence of these proteins, dsDNA unwinding and replisome movement powered by MCM2-7 continue, but DNA synthesis stops. At least part of this stop is due to the dissociation of polymerase ε from the replication fork.
Each subunit in the MCM structure contains two large N- and C-terminal domains. The N-terminal domain consists of three small sub-domains and appears to be used mainly for structural organization. The N-domain can coordinate with a neighboring subunit’s C-terminal AAA+ helicase domain through a long and conserved loop. This conserved loop, named the allosteric control loop, has been shown to play a role in regulating interactions between N- and C-terminal regions by facilitating communication between the domains in response to ATP hydrolysis . The N-domain also establishes the in vitro 3′→5′ directionality of MCM. 
Models of DNA unwinding by MCM2-7
Regarding the physical mechanism of how a hexameric helicase unwinds DNA, two models have been proposed based on in vivo and in vitro data. In the "steric" model, the helicase tightly translocates along one strand of DNA while physically displacing the complementary strand. In the "pump" model, pairs of hexameric helicases unwind duplex DNA by either twisting it apart or extruding it through channels in the complex.
The steric model hypothesizes that the helicase encircles dsDNA and, after local melting of the duplex DNA at the origin, translocates away from the origin, dragging a rigid proteinaceous "wedge" (either part of the helicase itself or another associated protein) that separates the DNA strands.
The pump model postulates that multiple helicases load at replication origins, translocate away from one another, and in some manner eventually become anchored in place. They then rotate dsDNA in opposite directions, resulting in the unwinding of the double helix in the intervening region.
Role in cancer
Various MCMs have been shown to promote cell proliferation in vitro and in vivo especially in certain types of cancer cell lines. The association between MCMs and proliferation in cancer cell lines is mostly attributed to its ability to enhance DNA replication. The roles of MCM2 and MCM7 in cell proliferation have been demonstrated in various cellular contexts and even in human specimens. 
MCM2 has been shown to be frequently expressed in proliferating premalignant lung cells. Its expression was associated with cells having a higher proliferation potential in non-dysplastic squamous epithelium, malignant fibrous histiocytomas, and endometrial carcinoma, while MCM2 expression was also correlated higher mitotic index in breast cancer specimens. 
Similarly, many research studies have shown the link between MCM7 expression and cell proliferation. Expression of MCM7 was significantly correlated with the expression of Ki67 in choriocarcinomas, lung cancer, papillary urothelial neoplasia, esophageal cancer, and endometrial cancer. Its expression was also associated with a higher proliferative index in prostatic intraepithelial neoplasia and cancer.
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