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Gene Review

MCM4  -  minichromosome maintenance complex...

Homo sapiens

Synonyms: CDC21, CDC21 homolog, CDC54, DNA replication licensing factor MCM4, MGC33310, ...
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Disease relevance of MCM4

  • MCM4 expression in esophageal cancer from southern China and its clinical significance [1].
  • Furthermore, MCM4 expression in esophageal carcinomas was significantly higher than the one in the adjacent epithelia (chi square value is 12.037, P < 0.001) [1].
  • Although MCMs are considered of utmost importance in tumor biology and as potential marker proteins, they were not unambiguously identified at the protein level and we therefore aimed to characterize MCM 4 in a medulloblastoma cell line and provide a protein chemical analytical tool [2].

High impact information on MCM4

  • Genetic evidence suggests that phosphorylation of Mcm4 by DDK is important for timely S phase progression and for cell viability upon overproduction of Cdc45 [3].
  • Such cells show a specific defect in loading of initiator proteins Mcm4, Mcm7, and to a lesser degree, Mcm2 onto chromatin during telophase and early G1 when Mcm2-7 are normally recruited to license origins of replication [4].
  • Thymine-rich single-stranded DNA activates Mcm4/6/7 helicase on Y-fork and bubble-like substrates [5].
  • The double heterohexameric complex of Mcm4/6/7, in the presence of a single-strand DNA binding protein, is capable of unwinding duplex DNA region of about 600 bp in length [6].
  • MCM-BP also formed a complex with the MCM4/6/7 core helicase in vitro, but, unlike MCM2, did not inhibit this helicase activity [7].

Biological context of MCM4

  • In addition, down-regulation of MCM-BP decreased the association of MCM4 with chromatin, and the chromatin association of MCM-BP was at least partially dependent on MCM4 and cdc6 [7].
  • MCM4 on the chromatin undergoes specific phosphorylation during S phase [8].
  • These results are consistent with the notion that the N-terminal phosphorylation of MCM2, MCM4, and MCM6 may play functionally redundant but essential roles in initiation of DNA replication [8].
  • MCM4 is an essential component of a protein complex that prevents DNA from being replicated more than once per cell cycle [9].
  • The promoters for human DNA-PKcs (PRKDC) and MCM4: divergently transcribed genes located at chromosome 8 band q11 [9].

Anatomical context of MCM4

  • We report here that human MCM4, a subunit of the putative DNA replicative helicase, is extensively phosphorylated in HeLa cells when they are incubated in the presence of inhibitors of DNA synthesis or are exposed to UV irradiation [10].

Associations of MCM4 with chemical compounds


Physical interactions of MCM4

  • Prereplication proteins Orc3p and Mcm4p bind to chromatin in the FMR1 initiation region in vivo [15].

Other interactions of MCM4

  • In a multivariable Cox model adjusted for tumor thickness, ulceration, age, and sex, expression of MCM4 (hazard ratio [HR] of death = 4.04, 95% confidence interval [CI] = 1.39 to 11.76; P = .010) and MCM6 (HR of death = 7.42, 95% CI = 1.99 to 27.64; P = .003) proteins was still statistically significantly associated with overall survival [16].
  • Thus, by modulating the phospho-status of MCM4 and regulating origin firing, S phase CDK2 appears to be an integrated component of cellular machinery required for temporally controlling replication activity and maintaining genomic stability [12].
  • Thus, the human Mcm-proteins Cdc21, Cdc46 and P1Mcm3 are not concentrated at sites of DNA replication [17].

Analytical, diagnostic and therapeutic context of MCM4


  1. MCM4 expression in esophageal cancer from southern China and its clinical significance. Huang, X.P., Rong, T.H., Wu, Q.L., Fu, J.H., Yang, H., Zhao, J.M., Fang, Y. J. Cancer Res. Clin. Oncol. (2005) [Pubmed]
  2. The medulloblastoma cell line DAOY but not eleven other tumor cell lines expresses minichromosome maintenance protein 4. Gruber-Olipitz, M., Yang, J.W., Stroebel, T., Slavc, I., Lubec, G. Cancer Lett. (2006) [Pubmed]
  3. Cdc7-Dbf4 Phosphorylates MCM Proteins via a Docking Site-Mediated Mechanism to Promote S Phase Progression. Sheu, Y.J., Stillman, B. Mol. Cell (2006) [Pubmed]
  4. Deregulation of cyclin E in human cells interferes with prereplication complex assembly. Ekholm-Reed, S., Méndez, J., Tedesco, D., Zetterberg, A., Stillman, B., Reed, S.I. J. Cell Biol. (2004) [Pubmed]
  5. Thymine-rich single-stranded DNA activates Mcm4/6/7 helicase on Y-fork and bubble-like substrates. You, Z., Ishimi, Y., Mizuno, T., Sugasawa, K., Hanaoka, F., Masai, H. EMBO J. (2003) [Pubmed]
  6. Processive DNA helicase activity of the minichromosome maintenance proteins 4, 6, and 7 complex requires forked DNA structures. Lee, J.K., Hurwitz, J. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  7. Identification and characterization of a novel component of the human minichromosome maintenance complex. Sakwe, A.M., Nguyen, T., Athanasopoulos, V., Shire, K., Frappier, L. Mol. Cell. Biol. (2007) [Pubmed]
  8. Phosphorylation of MCM4 by Cdc7 Kinase Facilitates Its Interaction with Cdc45 on the Chromatin. Masai, H., Taniyama, C., Ogino, K., Matsui, E., Kakusho, N., Matsumoto, S., Kim, J.M., Ishii, A., Tanaka, T., Kobayashi, T., Tamai, K., Ohtani, K., Arai, K. J. Biol. Chem. (2006) [Pubmed]
  9. The promoters for human DNA-PKcs (PRKDC) and MCM4: divergently transcribed genes located at chromosome 8 band q11. Connelly, M.A., Zhang, H., Kieleczawa, J., Anderson, C.W. Genomics (1998) [Pubmed]
  10. Identification of MCM4 as a target of the DNA replication block checkpoint system. Ishimi, Y., Komamura-Kohno, Y., Kwon, H.J., Yamada, K., Nakanishi, M. J. Biol. Chem. (2003) [Pubmed]
  11. Levels of MCM4 phosphorylation and DNA synthesis in DNA replication block checkpoint control. Ishimi, Y., Komamura-Kohno, Y., Karasawa-Shimizu, K., Yamada, K. J. Struct. Biol. (2004) [Pubmed]
  12. Human CDK2 inhibition modifies the dynamics of chromatin-bound minichromosome maintenance complex and replication protein A. Zhu, Y., Ishimi, Y., Tanudji, M., Lees, E. Cell Cycle (2005) [Pubmed]
  13. Stepwise regulated chromatin assembly of MCM2-7 proteins. Maiorano, D., Lemaître, J.M., Méchali, M. J. Biol. Chem. (2000) [Pubmed]
  14. Genome-wide expression profiling of the response to azole, polyene, echinocandin, and pyrimidine antifungal agents in Candida albicans. Liu, T.T., Lee, R.E., Barker, K.S., Lee, R.E., Wei, L., Homayouni, R., Rogers, P.D. Antimicrob. Agents Chemother. (2005) [Pubmed]
  15. An origin of DNA replication in the promoter region of the human fragile x mental retardation (FMR1) gene. Gray, S.J., Gerhardt, J., Doerfler, W., Small, L.E., Fanning, E. Mol. Cell. Biol. (2007) [Pubmed]
  16. Gene expression profiling of primary cutaneous melanoma and clinical outcome. Winnepenninckx, V., Lazar, V., Michiels, S., Dessen, P., Stas, M., Alonso, S.R., Avril, M.F., Ortiz Romero, P.L., Robert, T., Balacescu, O., Eggermont, A.M., Lenoir, G., Sarasin, A., Tursz, T., van den Oord, J.J., Spatz, A. J. Natl. Cancer Inst. (2006) [Pubmed]
  17. Human replication proteins hCdc21, hCdc46 and P1Mcm3 bind chromatin uniformly before S-phase and are displaced locally during DNA replication. Krude, T., Musahl, C., Laskey, R.A., Knippers, R. J. Cell. Sci. (1996) [Pubmed]
  18. Binding of human minichromosome maintenance proteins with histone H3. Ishimi, Y., Ichinose, S., Omori, A., Sato, K., Kimura, H. J. Biol. Chem. (1996) [Pubmed]
  19. MCM4 shares homology to a replication/DNA-binding domain in CTF and is contacted by pRb. Schmitz, N.M., Leibundgut, K., Hirt, A. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  20. Site-specific phosphorylation of MCM4 during the cell cycle in mammalian cells. Komamura-Kohno, Y., Karasawa-Shimizu, K., Saitoh, T., Sato, M., Hanaoka, F., Tanaka, S., Ishimi, Y. FEBS J. (2006) [Pubmed]
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