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Last update 08 May 2025

MCM4

Last update 08 May 2025

Basic Info

Synonyms

CDC21, CDC21 homolog, CDC54

+ [6]

Introduction

Acts as a component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. Core component of CDC45-MCM-GINS (CMG) helicase, the molecular machine that unwinds template DNA during replication, and around which the replisome is built (PubMed:16899510, PubMed:25661590, PubMed:32453425, PubMed:34694004, PubMed:34700328, PubMed:35585232, PubMed:9305914). The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity (PubMed:16899510, PubMed:25661590, PubMed:32453425, PubMed:9305914).

Drugs associated with MCM4

Emitefur

Target

MCM4

Mechanism

MCM4 antagonists

Active Org.-

Originator Org.

Otsuka Holdings Co., Ltd.

Active Indication-

Inactive Indication

Breast Cancer [+4]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with MCM4

100 Translational Medicine associated with MCM4

0 Patents (Medical) associated with MCM4

421

Literatures (Medical) associated with MCM4

01 Jun 2025·Prostaglandins & Other Lipid Mediators

E2F7 upregulates MCM4 and fatty acid metabolism to advance lung adenocarcinoma metastasis

Article

Author: Yang, Yalun ; Lei, Chenggang ; Xiao, Kuang ; Liu, Di ; Tang, WuAsen ; Zhou, Qian ; Zhang, Deming ; Wang, Xianghui ; Liu, Zikang

BACKGROUNDMCM4, a key protein in MCM, is frequently overexpressed in cancers, but its specific role in lung adenocarcinoma (LUAD) metastasis is unclear.METHODSBioinformatics revealed the mRNA expression pattern of MCM4 in LUAD, which we confirmed in both normal lung epithelial and adenocarcinoma cell lines using qRT-PCR and western blot (WB). Cellular proliferation was gauged by cell counting kit-8 and colony formation assays, and the expression of epithelial-mesenchymal transition markers along with fatty acid synthase (FASN) was probed via WB. We employed Transwell to assess cellular migration and invasion, and utilized kits for quantifying intracellular triglycerides and phospholipids. Bioinformatics identified E2F7 as a potential transcriptional regulator of MCM4, prompting us to explore its relationship with MCM4, including predicted binding sites and E2F7 mRNA expression in LUAD. Chromatin immunoprecipitation and dual-luciferase reporter assays were conducted to validate the regulatory effects of E2F7 on MCM4.RESULTSMCM4 was found to be overexpressed in LUAD, and its knockdown inhibited cancer cell proliferation, migration, invasion, and metastasis, along with decreased FASN expression and declined levels of triglycerides and phospholipids within cells. Mechanistically, E2F7 transcriptionally activated MCM4, regulating fatty acid metabolism and promoting LUAD progression and metastasis.CONCLUSIONOur study elucidates the mechanism by which E2F7 transcriptionally controls MCM4 to activate fatty acid metabolism, fueling LUAD metastasis. These discoveries emphasize the pivotal function of lipid metabolism in LUAD development and suggests new therapeutic targets for LUAD treatment.

01 Mar 2025·Advances in Medical Sciences

Recurrent hepatocellular carcinoma is associated with the enrichment of MYC targets gene sets, elevated high confidence deleterious mutations and alternative splicing of DDB2 and BRCA1 transcripts

Article

Author: Karaosmanoğlu, Oğuzhan

PURPOSERecurrence is the main cause of hepatocellular carcinoma (HCC) related deaths. Underlying recurrence biology can be better understood by comparative analysis of the complete set of transcripts between recurrent and non-recurrent HCC. In this study, transcriptomic data (GSE56545) from 21 male patients diagnosed with either recurrent or non-recurrent HCC were reanalyzed to identify deregulated pathways, somatic mutations, fusion transcripts, alternative splicing events, and the immune context in recurrent HCC.MATERIALS AND METHODSDESeq2 was used for differential expression analysis, Mutect2 for somatic mutation analysis, Arriba and STAR-Fusion for fusion transcript analysis, and rMATs for alternative splicing analysis.RESULTSThe results revealed that MYC targets gene sets (Hallmark_MYC_targets_V1 and Hallmark_MYC_targets_V2) were significantly enriched in recurrent HCC. Among the MYC targets, CBX3, NOP56, CDK4, NPM1, MCM5, MCM4 and PA2G4 upregulation was significantly associated with poor survival. Somatic mutation analysis demonstrated that the numbers of high confidence deleterious mutations were significantly increased in recurrent HCC. Alternative splicing-mediated production of non-functional DDB2 and oncogenic BRCA1 D11q were discovered in recurrent HCC. Finally, CD8⁺ T-cells were significantly decreased in recurrent HCC.CONCLUSIONSThese results indicated that the enrichment of MYC targets gene sets is one of the most critical factors that leads to the development of recurrent HCC. In addition, elevated deleterious mutation numbers and alternative spliced DDB2 and BRCA1 isoforms have been identified as prominent contributors to increasing genomic instability in male patients with recurrent HCC.

01 Mar 2025·Translational Cancer Research

The identification and prediction of lung adenocarcinoma prognosis using a novel gene signature associated with DNA replication

Article

Author: Xu, Qiang ; Aiyiti, Paerhati ; Citarella, Fabrizio ; Wu, Xiujuan ; Zhang, Jingang ; Meng, Defeng ; Christopoulos, Petros ; Liu, Tong ; Duan, Wei

BackgroundLung adenocarcinoma (LUAD) is the most aggressive lung cancer phenotype, and patients' clinical response is often limited by primary or acquired mechanisms of resistance to oncological therapy. One of the current clinical needs is to define clinical predictors for the prognosis of LUAD, aiming at offering patients a persistent treatment likely to delay disease progression as much as possible. This study relies on data from The Cancer Genome Atlas (TCGA) to define the functional roles and prognostic implications of DNA replication-related genes in LUAD.MethodsClinical features and RNA-sequencing data were collected from 607 LUAD patients from TCGA-LUAD dataset, with the aims to identify the genes related to patient prognosis, and the pathways related to DNA replication in LUAD.ResultsA total of 2,412 prognostic genes were obtained, and the DNA replication-related pathways closely associated with LUAD were identified by a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. TCGA-LUAD patients were divided into a high- (G1) and low- (G2) risk groups based on the 15 DNA replication-related genes (i.e., FEN1, MCM5, POLD2, MCM4, MCM6, SSBP1, POLE2, RFC2, MCM2, PCNA, POLA2, MCM7, RFC3, POLE4, and RPA3). The upregulated genes were mainly related to the hallmarks of cancer (e.g., chromosome segregation, DNA replication, the cell cycle checkpoint, and DNA helicase activity), while the downregulated genes were mainly related to leukocyte activation involved in inflammatory macrophage activation, and passive transmembrane transporter activity. The immune cells, including the B cells, endothelial cells, natural killer (NK) cells, cluster of differentiation (CD)4⁺ T cells, and CD8⁺ T cells, of the Group 1 (G1) LUAD samples were clearly different from those of the Group (G2) LUAD samples. In addition, 5 of the 10 immune checkpoint inhibitor (ICI)-related genes (i.e., CD274, LAG3, PDCD1, PDCD1LG2, and SIGLEC15) were of a higher level in the G1 LUAD samples than in the G2 LUAD samples. The tumor stemness of the two risk groups differed significantly. Furthermore, a six-gene (FEN1, MCM5, POLD2, MCM4, SSBP1, and POLE4) prognostic model was constructed to predict the prognosis of LUAD patients.ConclusionsThere is a close relationship between the DNA replication-related genes and the tumor classification of LUAD patients. An innovative signature related to DNA replication was found to be a good prognostic predictor of LUAD. Our findings may provide novel insights into the diagnosis and treatment of LUAD.

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MCM4

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