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

• We reported that MCM4, a subunit of a putative replicative DNA helicase, is extensively phosphorylated in the presence of hydroxyurea (HU) or after exposure to UV irradiation [11].
• We show that CDK2 suppression results in decreased MCM4 phosphorylation at multiple serine and threonine sites [12].
• Inhibition of licensing with 6-dimethylaminopurine results in chromatin containing specifically bound MCM4 and MCM6 [13].
• Flucytosine increased the expression of proteins involved in purine and pyrimidine biosynthesis, including YNK1, FUR1, and that encoding its target, CDC21 [14].

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

• Immunoprecipitation with anti-Cdc21 antibody revealed that these four MCM proteins form complexes [18].
• A new binding protein of under-phosphorylated pRb, MCM4, was identified using LexA-Rb(561-660) in the two-hybrid assay [19].
• In this study, we detected via RT-PCR the expression status of MCM4 in esophageal cancer from southern China and therefore disclose the relationship between MCM4 and esophageal cancer [1].
• Western blot analysis of HeLa cells indicated that phosphorylation of MCM4 at these seven sites can be classified into two groups: (a) phosphorylation that is greatly enhanced in the G2 and M phases (Thr7, Thr19, Ser32, Ser54, Ser88 and Thr110), and (b) phosphorylation that is firmly detected during interphase (Ser3) [20].

References