MCM6

DNA replication licensing factor MCM6 is a protein that in humans is encoded by the MCM6 gene.[5] MCM6 is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication.

MCM6
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2KLQ, 2LE8
Identifiers
Aliases	MCM6, MCG40308, Mis5, P105MCM, minichromosome maintenance complex component 6
External IDs	OMIM: 601806 MGI: 1298227 HomoloGene: 4322 GeneCards: MCM6
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q21.3 Start 135,839,626 bp[1] End 135,876,443 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1 E3|1 55.8 cM Start 128,331,590 bp[2] End 128,359,664 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • identical protein binding • single-stranded DNA binding • nucleotide binding • GO:0004003 DNA helicase activity • DNA binding • GO:0001948 protein binding • hydrolase activity • ATP binding • GO:0008026 helicase activity • DNA replication origin binding • single-stranded DNA-dependent ATP-dependent 3'-5' DNA helicase activity Cellular component • MCM complex • nuclear chromosome, telomeric region • cell nucleus • nucleoplasm Biological process • G1 phase • DNA replication • cell cycle • DNA replication initiation • DNA unwinding involved in DNA replication • G1/S transition of mitotic cell cycle • double-strand break repair via break-induced replication • pre-replicative complex assembly involved in nuclear cell cycle DNA replication • mitotic DNA replication Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4175	17219
Ensembl	ENSG00000076003	ENSMUSG00000026355
UniProt	Q14566	P97311
RefSeq (mRNA)	NM_005915	NM_008567 NM_001313695
RefSeq (protein)	NP_005906	NP_001300624 NP_032593
Location (UCSC)	Chr 2: 135.84 – 135.88 Mb	Chr 1: 128.33 – 128.36 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[6] 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.[7]

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.[8] The (-13910) region, in particular, has been shown to function in vitro as an enhancer element capable of differentially activating transcription of LCT promoter.[9]

Mutations in these regions are associated with lactose tolerance into adult life.[8][10]

Interactions

MCM6 has been shown to interact with:

• CDC45-related protein,[11]
• MCM2,[11][12][13][14][15]
• MCM4,[12][13][16]
• MCM7,[13][17]
• ORC1L,[11]
• ORC2L,[11]
• ORC4L,[11] and
• Replication protein A1.[11]

See also

• Mini Chromosome Maintenance

References

1. GRCh38: Ensembl release 89: ENSG00000076003 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000026355 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Harvey CB, Wang Y, Darmoul D, Phillips A, Mantei N, Swallow DM (December 1996). "Characterisation of a human homologue of a yeast cell division cycle gene, MCM6, located adjacent to the 5' end of the lactase gene on chromosome 2q21". FEBS Lett. 398 (2–3): 135–40. doi:10.1016/S0014-5793(96)01189-1. PMID 8977093.
6. "Entrez Gene: MCM6 minichromosome maintenance deficient 6 homolog (S. cerevisiae)".
7. Wei Z, Liu C, Wu X, Xu N, Zhou B, Liang C, Zhu G (March 2010). "Characterization and structure determination of the Cdt1 binding domain of human minichromosome maintenance (Mcm) 6". J Biol Chem. 285 (17): 12469–73. doi:10.1074/jbc.C109.094599. PMC 2857124. PMID 20202939.
8. Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Järvelä I (February 2002). "Identification of a variant associated with adult-type hypolactasia". Nat. Genet. 30 (2): 233–7. doi:10.1038/ng826. PMID 11788828.
9. Olds LC, Sibley E (September 2003). "Lactase persistence DNA variant enhances lactase promoter activity in vitro: functional role as a cis regulatory element". Hum. Mol. Genet. 12 (18): 2333–40. doi:10.1093/hmg/ddg244. PMID 12915462.
10. Mattar R, de Campos Mazo DF, Carrilho FJ (2012). "Lactose intolerance: diagnosis, genetic, and clinical factors". Clin Exp Gastroenterol. 5: 113–21. doi:10.2147/CEG.S32368. PMC 3401057. PMID 22826639. " Two variants were associated with lactase persistence..."
11. Kneissl M, Pütter V, Szalay AA, Grummt F (March 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.
12. Yabuta N, Kajimura N, Mayanagi K, Sato M, Gotow T, Uchiyama Y, Ishimi Y, Nojima H (May 2003). "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.
13. You Z, Ishimi Y, Masai H, Hanaoka F (November 2002). "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.
14. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
15. You Z, Komamura Y, Ishimi Y (December 1999). "Biochemical analysis of the intrinsic Mcm4-Mcm6-mcm7 DNA helicase activity". Mol. Cell. Biol. 19 (12): 8003–15. doi:10.1128/MCB.19.12.8003. PMC 84885. PMID 10567526.
16. Ishimi Y, Ichinose S, Omori A, Sato K, Kimura H (September 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.
17. Fujita M, Kiyono T, Hayashi Y, Ishibashi M (April 1997). "In vivo interaction of human MCM heterohexameric complexes with chromatin. Possible involvement of ATP". J. Biol. Chem. 272 (16): 10928–35. doi:10.1074/jbc.272.16.10928. PMID 9099751.

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. doi:10.1128/MCB.19.12.8003. 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.