Biology:MCM6
 Generic protein structure example |
DNA replication licensing factor MCM6 is a protein that in humans is encoded by the MCM6 gene.[1] 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.[2] 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.[3]
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.[4] 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.[5]
Mutations in these regions are associated with lactose tolerance into adult life.[4][6]
Interactions
MCM6 has been shown to interact with:
- CDC45-related protein,[7]
- MCM2,[7][8][9][10][11]
- MCM4,[8][9][12]
- MCM7,[9][13]
- ORC1L,[7]
- ORC2L,[7]
- ORC4L,[7] and
- Replication protein A1.[7]
See also
- Mini Chromosome Maintenance
References
- ↑ "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. December 1996. doi:10.1016/S0014-5793(96)01189-1. PMID 8977093.
- ↑ "Entrez Gene: MCM6 minichromosome maintenance deficient 6 homolog (S. cerevisiae)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4175.
- ↑ "Characterization and structure determination of the Cdt1 binding domain of human minichromosome maintenance (Mcm) 6". J Biol Chem 285 (17): 12469–73. March 2010. doi:10.1074/jbc.C109.094599. PMID 20202939.
- ↑ 4.0 4.1 "Identification of a variant associated with adult-type hypolactasia". Nat. Genet. 30 (2): 233–7. February 2002. doi:10.1038/ng826. PMID 11788828.
- ↑ "Lactase persistence DNA variant enhances lactase promoter activity in vitro: functional role as a cis regulatory element". Hum. Mol. Genet. 12 (18): 2333–40. September 2003. doi:10.1093/hmg/ddg244. PMID 12915462.
- ↑ "Lactose intolerance: diagnosis, genetic, and clinical factors". Clin Exp Gastroenterol 5: 113–21. 2012. doi:10.2147/CEG.S32368. PMID 22826639. " Two variants were associated with lactase persistence..."
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 "Interaction and assembly of murine pre-replicative complex proteins in yeast and mouse cells". J. Mol. Biol. 327 (1): 111–28. March 2003. doi:10.1016/s0022-2836(03)00079-2. PMID 12614612.
- ↑ 8.0 8.1 "Mammalian Mcm2/4/6/7 complex forms a toroidal structure". Genes Cells 8 (5): 413–21. May 2003. doi:10.1046/j.1365-2443.2003.00645.x. PMID 12694531.
- ↑ 9.0 9.1 9.2 "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. November 2002. doi:10.1074/jbc.M205769200. PMID 12207017.
- ↑ "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. October 2005. doi:10.1038/nature04209. PMID 16189514. Bibcode: 2005Natur.437.1173R.
- ↑ "Biochemical analysis of the intrinsic Mcm4-Mcm6-mcm7 DNA helicase activity". Mol. Cell. Biol. 19 (12): 8003–15. December 1999. doi:10.1128/MCB.19.12.8003. PMID 10567526.
- ↑ "Binding of human minichromosome maintenance proteins with histone H3". J. Biol. Chem. 271 (39): 24115–22. September 1996. doi:10.1074/jbc.271.39.24115. PMID 8798650.
- ↑ "In vivo interaction of human MCM heterohexameric complexes with chromatin. Possible involvement of ATP". J. Biol. Chem. 272 (16): 10928–35. April 1997. doi:10.1074/jbc.272.16.10928. PMID 9099751.
Further reading
- "Binding of human minichromosome maintenance proteins with histone H3". J. Biol. Chem. 271 (39): 24115–22. 1996. doi:10.1074/jbc.271.39.24115. PMID 8798650.
- "A novel human Mcm protein: homology to the yeast replication protein Mis5 and chromosomal location". Genomics 37 (1): 131–4. 1997. doi:10.1006/geno.1996.0530. PMID 8921380.
- "HsMCM6: a new member of the human MCM/P1 family encodes a protein homologous to fission yeast Mis5". Genes Cells 2 (6): 381–99. 1997. doi:10.1046/j.1365-2443.1997.1290327.x. PMID 9286856.
- "A DNA helicase activity is associated with an MCM4, -6, and -7 protein complex". J. Biol. Chem. 272 (39): 24508–13. 1997. doi:10.1074/jbc.272.39.24508. PMID 9305914.
- "Human protein MCM6 on HeLa cell chromatin". J. Biol. Chem. 273 (13): 7320–5. 1998. doi:10.1074/jbc.273.13.7320. PMID 9516426.
- "Cell growth-regulated expression of mammalian MCM5 and MCM6 genes mediated by the transcription factor E2F". Oncogene 18 (14): 2299–309. 1999. doi:10.1038/sj.onc.1202544. PMID 10327050.
- "Biochemical analysis of the intrinsic Mcm4-Mcm6-mcm7 DNA helicase activity". Mol. Cell. Biol. 19 (12): 8003–15. 2000. doi:10.1128/MCB.19.12.8003. PMID 10567526.
- "Inhibition of Mcm4,6,7 helicase activity by phosphorylation with cyclin A/Cdk2". J. Biol. Chem. 275 (21): 16235–41. 2000. doi:10.1074/jbc.M909040199. PMID 10748114.
- "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. 2001. doi:10.1093/nar/28.23.4769. PMID 11095689.
- "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. 2001. doi:10.1073/pnas.98.1.54. PMID 11136247. Bibcode: 2001PNAS...98...54L.
- "Identification of a variant associated with adult-type hypolactasia". Nat. Genet. 30 (2): 233–7. 2002. doi:10.1038/ng826. PMID 11788828.
- "Mouse geminin inhibits not only Cdt1-MCM6 interactions but also a novel intrinsic Cdt1 DNA binding activity". J. Biol. Chem. 277 (43): 40871–80. 2002. doi:10.1074/jbc.M206202200. PMID 12192004.
- "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. 2003. doi:10.1074/jbc.M205769200. PMID 12207017.
- "Interaction and assembly of murine pre-replicative complex proteins in yeast and mouse cells". J. Mol. Biol. 327 (1): 111–28. 2003. doi:10.1016/S0022-2836(03)00079-2. PMID 12614612.
- "Mammalian Mcm2/4/6/7 complex forms a toroidal structure". Genes Cells 8 (5): 413–21. 2004. doi:10.1046/j.1365-2443.2003.00645.x. PMID 12694531.
- "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. 2003. doi:10.1093/nar/gkg395. PMID 12771218.
- "Self-assembling protein microarrays". Science 305 (5680): 86–90. 2004. doi:10.1126/science.1097639. PMID 15232106. Bibcode: 2004Sci...305...86R.
- "Pairwise interactions of the six human MCM protein subunits". J. Mol. Biol. 340 (5): 1197–206. 2004. doi:10.1016/j.jmb.2004.05.024. PMID 15236977.
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