MCM4 explained

DNA replication licensing factor MCM4 is a protein that in humans is encoded by the MCM4 gene.^[1]

Function

The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by 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 MCM complex consisting of this protein and MCM2, 6 and 7 proteins possesses DNA helicase activity, and may act as a DNA unwinding enzyme. The phosphorylation of this protein by CDC2 kinase reduces the DNA helicase activity and chromatin binding of the MCM complex. This gene is mapped to a region on the chromosome 8 head-to-head next to the PRKDC/DNA-PK, a DNA-activated protein kinase involved in the repair of DNA double-strand breaks. Alternatively spliced transcript variants encoding the same protein have been reported.^[2]

See also

• Mini Chromosome Maintenance

Interactions

MCM4 has been shown to interact with:

• Cell division cycle 7-related protein kinase,
• MCM2,^[3]
• MCM6,^{[4] [5] [6]}
• MCM7,^{[4] [5] [6] [7]}
• ORC1L,^[8]
• ORC2L,^[8]
• ORC3L,^[8]
• ORC4L,^[8]
• ORC5L,^[8]
• ORC6L,^[8] and
• Replication protein A1.^[8]

Further reading

• Hu B, Burkhart R, Schulte D, Musahl C, Knippers R . The P1 family: a new class of nuclear mammalian proteins related to the yeast Mcm replication proteins . Nucleic Acids Res. . 21 . 23 . 5289–93 . 1994 . 8265339 . 310560 . 10.1093/nar/21.23.5289-a .
• Schulte D, Richter A, Burkhart R, Musahl C, Knippers R . Properties of the human nuclear protein p85Mcm. Expression, nuclear localization and interaction with other Mcm proteins . Eur. J. Biochem. . 235 . 1–2 . 144–51 . 1996 . 8631321 . 10.1111/j.1432-1033.1996.00144.x . free .
• Ishimi Y, Ichinose S, Omori A, Sato K, Kimura H . Binding of human minichromosome maintenance proteins with histone H3 . J. Biol. Chem. . 271 . 39 . 24115–22 . 1996 . 8798650 . 10.1074/jbc.271.39.24115 . free .
• Ladenburger EM, Fackelmayer FO, Hameister H, Knippers R . MCM4 and PRKDC, human genes encoding proteins MCM4 and DNA-PKcs, are close neighbours located on chromosome 8q12→q13 . Cytogenet. Cell Genet. . 77 . 3–4 . 268–70 . 1997 . 9284934 . 10.1159/000134594 .
• Ishimi Y . A DNA helicase activity is associated with an MCM4, -6, and -7 protein complex . J. Biol. Chem. . 272 . 39 . 24508–13 . 1997 . 9305914 . 10.1074/jbc.272.39.24508 . free .
• Connelly MA, Zhang H, Kieleczawa J, Anderson CW . The promoters for human DNA-PKcs (PRKDC) and MCM4: divergently transcribed genes located at chromosome 8 band q11 . Genomics . 47 . 1 . 71–83 . 1998 . 9465298 . 10.1006/geno.1997.5076 .
• Fujita M, Yamada C, Tsurumi T, Hanaoka F, Matsuzawa K, Inagaki M . Cell cycle- and chromatin binding state-dependent phosphorylation of human MCM heterohexameric complexes. A role for cdc2 kinase . J. Biol. Chem. . 273 . 27 . 17095–101 . 1998 . 9642275 . 10.1074/jbc.273.27.17095 . free .
• You Z, Komamura Y, Ishimi Y . Biochemical Analysis of the Intrinsic Mcm4-Mcm6-Mcm7 DNA Helicase Activity . Mol. Cell. Biol. . 19 . 12 . 8003–15 . 2000 . 10567526 . 84885 . 10.1128/MCB.19.12.8003.
• Ishimi Y, Komamura-Kohno Y, You Z, Omori A, Kitagawa M . Inhibition of Mcm4,6,7 helicase activity by phosphorylation with cyclin A/Cdk2 . J. Biol. Chem. . 275 . 21 . 16235–41 . 2000 . 10748114 . 10.1074/jbc.M909040199 . free .
• Izumi M, Yanagi K, Mizuno T, Yokoi M, Kawasaki Y, Moon KY, Hurwitz J, Yatagai F, Hanaoka F . The human homolog of Saccharomyces cerevisiae Mcm10 interacts with replication factors and dissociates from nuclease-resistant nuclear structures in G2 phase . Nucleic Acids Res. . 28 . 23 . 4769–77 . 2001 . 11095689 . 115166 . 10.1093/nar/28.23.4769 .
• Lee JK, Hurwitz J . 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 . 11136247 . 14543 . 10.1073/pnas.98.1.54 . 2001PNAS...98...54L . free .
• Ishimi Y, Komamura-Kohno Y . Phosphorylation of Mcm4 at specific sites by cyclin-dependent kinase leads to loss of Mcm4,6,7 helicase activity . J. Biol. Chem. . 276 . 37 . 34428–33 . 2001 . 11454864 . 10.1074/jbc.M104480200 . free .
• You Z, Ishimi Y, Masai H, Hanaoka F . 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 . 12207017 . 10.1074/jbc.M205769200 . free .
• Kneissl M, Pütter V, Szalay AA, Grummt F . Interaction and assembly of murine pre-replicative complex proteins in yeast and mouse cells . J. Mol. Biol. . 327 . 1 . 111–28 . 2003 . 12614612 . 10.1016/S0022-2836(03)00079-2 .
• Yabuta N, Kajimura N, Mayanagi K, Sato M, Gotow T, Uchiyama Y, Ishimi Y, Nojima H . Mammalian Mcm2/4/6/7 complex forms a toroidal structure . Genes Cells . 8 . 5 . 413–21 . 2004 . 12694531 . 10.1046/j.1365-2443.2003.00645.x . 27707848 . free .
• Ishimi Y, Komamura-Kohno Y, Kwon HJ, Yamada K, Nakanishi M . Identification of MCM4 as a target of the DNA replication block checkpoint system . J. Biol. Chem. . 278 . 27 . 24644–50 . 2003 . 12714602 . 10.1074/jbc.M213252200 . free .
• Johnson EM, Kinoshita Y, Daniel DC . 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 . 12771218 . 156728 . 10.1093/nar/gkg395 .

Notes and References

1. Musahl C, Schulte D, Burkhart R, Knippers R . A human homologue of the yeast replication protein Cdc21. Interactions with other Mcm proteins . Eur J Biochem . 230 . 3 . 1096–101 . August 1995 . 7601140 . 10.1111/j.1432-1033.1995.tb20660.x .
2. Web site: Entrez Gene: MCM4 MCM4 minichromosome maintenance deficient 4 (S. cerevisiae).
3. You Z, Komamura Y, Ishimi Y . Biochemical analysis of the intrinsic Mcm4-Mcm6-mcm7 DNA helicase activity . Mol. Cell. Biol. . 19 . 12 . 8003–15 . December 1999 . 10567526 . 84885 . 10.1128/MCB.19.12.8003.
4. Yabuta N, Kajimura N, Mayanagi K, Sato M, Gotow T, Uchiyama Y, Ishimi Y, Nojima H . Mammalian Mcm2/4/6/7 complex forms a toroidal structure . Genes Cells . 8 . 5 . 413–21 . May 2003 . 12694531 . 10.1046/j.1365-2443.2003.00645.x. 27707848 . free .
5. Ishimi Y, Ichinose S, Omori A, Sato K, Kimura H . Binding of human minichromosome maintenance proteins with histone H3 . J. Biol. Chem. . 271 . 39 . 24115–22 . September 1996 . 8798650 . 10.1074/jbc.271.39.24115. free .
6. You Z, Ishimi Y, Masai H, Hanaoka F . 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 . 12207017 . 10.1074/jbc.M205769200 . free .
7. Fujita M, Kiyono T, Hayashi Y, Ishibashi M . In vivo interaction of human MCM heterohexameric complexes with chromatin. Possible involvement of ATP . J. Biol. Chem. . 272 . 16 . 10928–35 . April 1997 . 9099751 . 10.1074/jbc.272.16.10928. free .
8. Kneissl M, Pütter V, Szalay AA, Grummt F . Interaction and assembly of murine pre-replicative complex proteins in yeast and mouse cells . J. Mol. Biol. . 327 . 1 . 111–28 . March 2003 . 12614612 . 10.1016/s0022-2836(03)00079-2.