MCM6

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; OMA:MCM6 - orthologs
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 128,259,327 bp [2] End 128,287,401 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ventricular zone embryo ganglionic eminence trabecular bone endothelial cell gonad glomerulus secondary oocyte metanephric glomerulus bone marrow Top expressed in somite Paneth cell mandibular prominence abdominal wall hand maxillary prominence fetal liver hematopoietic progenitor cell primitive streak Gonadal ridge efferent ductule More reference expression data BioGPS More reference expression data
Gene ontology Molecular function identical protein binding single-stranded DNA binding nucleotide binding DNA helicase activity DNA binding protein binding hydrolase activity ATP binding helicase activity DNA replication origin binding single-stranded 3'-5' DNA helicase activity Cellular component MCM complex 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: 128.26 – 128.29 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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 is 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. ^[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 and 22 kb upstream of LCT. ^[8] A substitution of thymine for cytosine in the first region (at -13910), 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. S2CID   1323113.
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. S2CID   21430931.
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. S2CID   27707848.
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. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID   16189514. S2CID   4427026.
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. S2CID   12997515.
• 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. Bibcode:2001PNAS...98...54L. 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. S2CID   21430931.
• 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. S2CID   27707848.
• 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. Bibcode:2004Sci...305...86R. doi:10.1126/science.1097639. PMID   15232106. S2CID   20936301.
• 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.