MCM6

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External IDs	GeneCards: [1]
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Species	Human	Mouse
Entrez	n/a	n/a
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RefSeq (mRNA)	n/a	n/a
RefSeq (protein)	n/a	n/a
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DNA replication licensing factor MCM6 is a protein that in humans is encoded by the MCM6 gene. MCM6 is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication.

Function

The MCM complex consisting of MCM6 (this protein) and MCM2, 4 and 7 possesses DNA helicase activity, and may act as a DNA unwinding enzyme. The hexameric protein complex formed by the MCM proteins is a key component of the pre-replication complex (pre-RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. The phosphorylation of the complex by CDC2 kinase reduces the helicase activity, suggesting a role in the regulation of DNA replication. Mcm 6 has recently been shown to interact strongly Cdt1 at defined residues, by mutating these target residues Wei et al. observed lack of Cdt1 recruitment of Mcm2-7 to the pre-RC.

Gene

The MCM6 gene, MCM6, is expressed at very high level. MCM6 contains 18 introns. There are 2 non overlapping alternative last exons. The transcripts appear to differ by truncation of the 3' end, presence or absence of 2 cassette exons, common exons with different boundaries.

MCM6 produces, by alternative splicing, 3 different transcripts, all with introns, putatively encoding 3 different protein isoforms.

MCM6 contains two of the regulatory regions for LCT, the gene encoding the protein lactase, located in two of the MCM6 introns, approximately 14 kb (-13910) and 22 kb (-22018) upstream of LCT. The (-13910) region, in particular, has been shown to function in vitro as an enhancer element capable of differentially activating transcription of LCT promoter.

Mutations in these regions are associated with lactose tolerance into adult life.

Interactions

MCM6 has been shown to interact with:

• CDC45-related protein,
• MCM2,
• MCM4,
• MCM7,
• ORC1L,
• ORC2L,
• ORC4L, and
• Replication protein A1.

See also

• Mini Chromosome Maintenance

Further reading

• Ishimi Y, Ichinose S, Omori A, Sato K, Kimura H (1996). "Binding of human minichromosome maintenance proteins with histone H3". J. Biol. Chem. 271 (39): 24115–22. doi:10.1074/jbc.271.39.24115. PMID 8798650.
• Holthoff HP, Hameister H, Knippers R (1997). "A novel human Mcm protein: homology to the yeast replication protein Mis5 and chromosomal location". Genomics. 37 (1): 131–4. doi:10.1006/geno.1996.0530. PMID 8921380.
• Tsuruga H, Yabuta N, Hosoya S, Tamura K, Endo Y, Nojima H (1997). "HsMCM6: a new member of the human MCM/P1 family encodes a protein homologous to fission yeast Mis5". Genes Cells. 2 (6): 381–99. doi:10.1046/j.1365-2443.1997.1290327.x. PMID 9286856.
• Ishimi Y (1997). "A DNA helicase activity is associated with an MCM4, -6, and -7 protein complex". J. Biol. Chem. 272 (39): 24508–13. doi:10.1074/jbc.272.39.24508. PMID 9305914.
• Holthoff HP, Baack M, Richter A, Ritzi M, Knippers R (1998). "Human protein MCM6 on HeLa cell chromatin". J. Biol. Chem. 273 (13): 7320–5. doi:10.1074/jbc.273.13.7320. PMID 9516426.
• Ohtani K, Iwanaga R, Nakamura M, Ikeda M, Yabuta N, Tsuruga H, Nojima H (1999). "Cell growth-regulated expression of mammalian MCM5 and MCM6 genes mediated by the transcription factor E2F". Oncogene. 18 (14): 2299–309. doi:10.1038/sj.onc.1202544. PMID 10327050.
• You Z, Komamura Y, Ishimi Y (2000). "Biochemical analysis of the intrinsic Mcm4-Mcm6-mcm7 DNA helicase activity". Mol. Cell. Biol. 19 (12): 8003–15. PMC 84885. PMID 10567526.
• Ishimi Y, Komamura-Kohno Y, You Z, Omori A, Kitagawa M (2000). "Inhibition of Mcm4,6,7 helicase activity by phosphorylation with cyclin A/Cdk2". J. Biol. Chem. 275 (21): 16235–41. doi:10.1074/jbc.M909040199. PMID 10748114.
• Izumi M, Yanagi K, Mizuno T, Yokoi M, Kawasaki Y, Moon KY, Hurwitz J, Yatagai F, Hanaoka F (2001). "The human homolog of Saccharomyces cerevisiae Mcm10 interacts with replication factors and dissociates from nuclease-resistant nuclear structures in G(2) phase". Nucleic Acids Res. 28 (23): 4769–77. doi:10.1093/nar/28.23.4769. PMC 115166. PMID 11095689.
• Lee JK, Hurwitz J (2001). "Processive DNA helicase activity of the minichromosome maintenance proteins 4, 6, and 7 complex requires forked DNA structures". Proc. Natl. Acad. Sci. U.S.A. 98 (1): 54–9. doi:10.1073/pnas.98.1.54. PMC 14543. PMID 11136247.
• Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Järvelä I (2002). "Identification of a variant associated with adult-type hypolactasia". Nat. Genet. 30 (2): 233–7. doi:10.1038/ng826. PMID 11788828.
• Yanagi K, Mizuno T, You Z, Hanaoka F (2002). "Mouse geminin inhibits not only Cdt1-MCM6 interactions but also a novel intrinsic Cdt1 DNA binding activity". J. Biol. Chem. 277 (43): 40871–80. doi:10.1074/jbc.M206202200. PMID 12192004.
• You Z, Ishimi Y, Masai H, Hanaoka F (2003). "Roles of Mcm7 and Mcm4 subunits in the DNA helicase activity of the mouse Mcm4/6/7 complex". J. Biol. Chem. 277 (45): 42471–9. doi:10.1074/jbc.M205769200. PMID 12207017.
• Kneissl M, Pütter V, Szalay AA, Grummt F (2003). "Interaction and assembly of murine pre-replicative complex proteins in yeast and mouse cells". J. Mol. Biol. 327 (1): 111–28. doi:10.1016/S0022-2836(03)00079-2. PMID 12614612.
• Yabuta N, Kajimura N, Mayanagi K, Sato M, Gotow T, Uchiyama Y, Ishimi Y, Nojima H (2004). "Mammalian Mcm2/4/6/7 complex forms a toroidal structure". Genes Cells. 8 (5): 413–21. doi:10.1046/j.1365-2443.2003.00645.x. PMID 12694531.
• Johnson EM, Kinoshita Y, Daniel DC (2003). "A new member of the MCM protein family encoded by the human MCM8 gene, located contrapodal to GCD10 at chromosome band 20p12.3-13". Nucleic Acids Res. 31 (11): 2915–25. doi:10.1093/nar/gkg395. PMC 156728. PMID 12771218.
• Ramachandran N, Hainsworth E, Bhullar B, Eisenstein S, Rosen B, Lau AY, Walter JC, LaBaer J (2004). "Self-assembling protein microarrays". Science. 305 (5680): 86–90. doi:10.1126/science.1097639. PMID 15232106.
• Yu Z, Feng D, Liang C (2004). "Pairwise interactions of the six human MCM protein subunits". J. Mol. Biol. 340 (5): 1197–206. doi:10.1016/j.jmb.2004.05.024. PMID 15236977.