RUNX1 regulates MCM2/CDC20 to promote COAD progression modified by deubiquitination of USP31.

Colon adenocarcinoma (COAD) is the second leading cause of cancer death, and there is still a lack of diagnostic biomarkers and therapeutic targets. In this study, bioinformatics analysis of the TCGA database was used to obtain RUNX1, a gene with prognostic value in COAD. RUNX1 plays an important role in many malignancies, and its molecular regulatory mechanisms in COAD remain to be fully understood. To explore the physiological role of RUNX1, we performed functional analyses, such as CCK-8, colony formation and migration assays. In addition, we investigated the underlying mechanisms using transcriptome sequencing and chromatin immunoprecipitation assays. RUNX1 is highly expressed in COAD patients and significantly correlates with survival. Silencing of RUNX1 significantly slowed down the proliferation and migratory capacity of COAD cells. Furthermore, we demonstrate that CDC20 and MCM2 may be target genes of RUNX1, and that RUNX1 may be physically linked to the deubiquitinating enzyme USP31, which mediates the upregulation of RUNX1 protein to promote transcriptional function. Our results may provide new insights into the mechanism of action of RUNX1 in COAD and reveal potential therapeutic targets for this disease.

DNAJC9 prevents CENP-A mislocalization and chromosomal instability by maintaining the fidelity of histone supply chains.

The centromeric histone H3 variant CENP-A is overexpressed in many cancers. The mislocalization of CENP-A to noncentromeric regions contributes to chromosomal instability (CIN), a hallmark of cancer. However, pathways that promote or prevent CENP-A mislocalization remain poorly defined. Here, we performed a genome-wide RNAi screen for regulators of CENP-A localization which identified DNAJC9, a J-domain protein implicated in histone H3-H4 protein folding, as a factor restricting CENP-A mislocalization. Cells lacking DNAJC9 exhibit mislocalization of CENP-A throughout the genome, and CIN phenotypes. Global interactome analysis showed that DNAJC9 depletion promotes the interaction of CENP-A with the DNA-replication-associated histone chaperone MCM2. CENP-A mislocalization upon DNAJC9 depletion was dependent on MCM2, defining MCM2 as a driver of CENP-A deposition at ectopic sites when H3-H4 supply chains are disrupted. Cells depleted for histone H3.3, also exhibit CENP-A mislocalization. In summary, we have defined novel factors that prevent mislocalization of CENP-A, and demonstrated that the integrity of H3-H4 supply chains regulated by histone chaperones such as DNAJC9 restrict CENP-A mislocalization and CIN.

Regulation of cancer stem cells by CXCL1, a chemokine whose secretion is controlled by MCM2.

BACKGROUND: A high expression pattern of minichromosome maintenance 2 (MCM2) has been observed in various cancers. MCM2 is a protein involved in the cell cycle and plays a role in cancer growth and differentiation by binding to six members of the MCM subfamily. The MCM protein family includes MCM2 through MCM7. METHODS: MCM2 has shown high expression in both lung cancer stem cells (LCSCs) and glioma stem cells (GSCs). We investigated the characteristics of CSCs and the regulation of the epithelial-to-mesenchymal transition (EMT) phenomenon in LCSCs and GSCs by MCM2. Additionally, we explored secreted factors regulated by MCM2. RESULTS: There was a significant difference in survival rates between lung cancer patients and brain cancer patients based on MCM2 expression. MCM2 was found to regulate both markers and regulatory proteins in LCSCs. Moreover, MCM2 is thought to be involved in cancer metastasis by regulating cell migration and invasion, not limited to lung cancer but also identified in glioma. Among chemokines, chemokine (C-X-C motif) ligand 1 (CXCL1) was found to be regulated by MCM2. CONCLUSIONS: MCM2 not only participates in the cell cycle but also affects cancer cell growth by regulating the external microenvironment to create a favorable environment for cells. MCM2 is highly expressed in malignant carcinomas, including CSCs, and contributes to the malignancy of various cancers. Therefore, MCM2 may represent a crucial target for cancer therapeutics.

MCM2 is involved in subtyping and tamoxifen resistance of ERα-positive breast cancer by acting as the downstream factor of ERα.

Tamoxifen (TAM) resistance is finally developed in over 40% of patients with estrogen receptor α-positive breast cancer (ERα+ -BC), documenting that discovering new molecular subtype is needed to confer perception to the heterogeneity of ERα+ -BC. We obtained representative gene sets subtyping ERα+ -BC using gene set variation analysis (GSVA), non-negative matrix factorization (NMF), and COX regression methods on the basis of METABRIC, TCGA, and GEO databases. Furthermore, the risk score of ERα+ -BC subtyping was established using least absolute shrinkage and selection operator (LASSO) regression on the basis of genes in the representative gene sets, thereby generating the two subtypes of ERα+ -BC. We further found that minichromosome maintenance complex component 2 (MCM2) functioned as the hub gene subtyping ERα+ -BC using GO, KEGG, and MCODE. MCM2 expression was capable for specifically predicting 1-year overall survival (OS) of ERα+ -BC and correlated with T stage, AJCC stage, and tamoxifen (TAM) sensitivity of ERα+ -BC. The downregulation of MCM2 expression inhibited proliferation, migration, and invasion of TAM-resistant cells and promoted G0/G1 arrest. Altogether, tamoxifen resistance entails that MCM2 is a hub gene subtyping ERα+ -BC, providing a novel dimension for discovering a potential target of TAM-resistant BC.

MCM2 promotes the stemness of endometrial cancer cells via the Akt/ß-catenin pathway.

Minichromosome maintenance complex component 2 (MCM2) is a member of the MCM family and is involved in various cancers. However, the role of MCM2 in endometrial cancer (EC) remains unclear. In this study, we aim to determine the biological function of MCM2 in EC cells and identify the potential underlying mechanisms. MCM2 expression and prognostic significance were analyzed in TCGA-UCEC datasets. Combining bioinformatics analyses and experiments, stemness-related molecules and phenotypes were examined to evaluate the impact of MCM2 on stemness in EC cells. The major findings of these analyses are as follows: 1) MCM2 is expressed at higher levels in EC tissues than in normal endometrial tissues. High expression of MCM2 is related to the characteristics of poorly differentiated EC. High MCM2 expression is correlated with poor overall survival in EC patients; 2) MCM2 knockdown was found to decrease sphere formation ability, downregulate the expression of stemness-related molecules, and reduce the proportion of CD133+ cells, while MCM2 overexpression elicited the opposite effect in EC cells; 3) MCM2-mediated stemness features are dependent on the activation of Akt/ß-catenin signaling pathways; and 4) MCM2 knockdown increases cisplatin sensitivity in EC cells. MCM2 regulates stemness by regulating the Akt/ß-catenin signaling pathway in EC cells.

Coiled-coil domain-containing 154 promotes colorectal cancer proliferation and metastasis via interacting with minichromosome maintenance complex component 2.

Coiled-Coil Domain-Containing (CCDC) is a large class of structural proteins containing left-handed supercoiled structure. The clinical value and the functional implication of CCDC in colorectal cancer (CRC) remain unknown. Based on the genetic, transcriptional, and clinical data from The Cancer Genome Atlas, five of thirty-six CCDC proteins were differentially expressed in the CRC and associated with the survival of patients with CRC. A CCDC-score model was established to evaluate the prognosis of patients. The potential function of Coiled-Coil Domain-Containing 154 (CCDC154) was investigated using bioinformatical methods, which unveiled that high expression of CCDC154 indicates poor survival for patients with CRC and correlates with low infiltration of CD8+ T cells and high infiltration of neutrophils, indicating that CCDC154 enhances tumor growth and metastasis. CCDC154 interacts with Minichromosome Maintenance Complex Component 2 (MCM2) protein and promotes malignant phenotype via MCM2. We validated the expression level and survival prediction value of CCDC154 in clinical samples, and analyzed its co-expression of MCM2, Ki-67 and p53. This work discloses the role of CCDC in clinical setting and CCDC154 functions in CRC.

Characterization of histone chaperone MCM2 as a key regulator in arsenic-induced depletion of H3.3 at genomic loci.

Arsenic exposure is associated with an increased risk of many cancers, and epigenetic mechanisms play a crucial role in arsenic-mediated carcinogenesis. Our previous studies have shown that arsenic exposure induces polyadenylation of H3.1 mRNA and inhibits the deposition of H3.3 at critical gene regulatory elements. However, the precise underling mechanisms are not yet understood. To characterize the factors governing arsenic-induced inhibition of H3.3 assembly through H3.1 mRNA polyadenylation, we utilized mass spectrometry to identify the proteins, especially histone chaperones, with reduced binding affinity to H3.3 under conditions of arsenic exposure and polyadenylated H3.1 mRNA overexpression. Our findings reveal that the interaction between H3.3 and the histone chaperon protein MCM2 is diminished by both polyadenylated H3.1 mRNA overexpression and arsenic treatment in human lung epithelial BEAS-2B cells. The increased binding of MCM2 to H3.1, resulting from elevated H3.1 protein levels, appears to contribute to the reduced availability of MCM2 for H3.3. To further investigate the role of MCM2 in H3.3 deposition during arsenic exposure and H3.1 mRNA polyadenylation, we overexpressed MCM2 in BEAS-2B cells overexpressing polyadenylated H3.1 or exposed to arsenic. Our results demonstrate that MCM2 overexpression attenuates H3.3 depletion at several genomic loci, suggesting its involvement in the arsenic-induced displacement of H3.3 mediated by H3.1 mRNA polyadenylation. These findings suggest that changes in the association between histone chaperone MCM2 and H3.3 due to polyadenylation of H3.1 mRNA may play a pivotal role in arsenic-induced carcinogenesis.

KNTC1 and MCM2 are the molecular targets of gallbladder cancer.

BACKGROUND: Gallbladder carcinoma is a malignant epithelial tumor of gallbladder with a high degree of malignancy. However, relationship between KNTC1 and MCM2 and gallbladder cancer is unclear. METHODS: GSE139682 and GSE202479 were downloaded from gene expression omnibus (GEO). Differentially expressed genes (DEGs) were screened. Functional enrichment analysis and gene set enrichment analysis (GSEA) were performed. Protein-protein interaction (PPI) Network was constructed and analyzed. Gene expression heat map was drawn. Comparative toxicogenomics database (CTD) analysis was performed to find diseases most related to core genes. TargetScan was performed for screening miRNAs that regulated central DEGs. RESULTS: 230 DEGs were identified. According to GObp analysis, they were mainly concentrated in regulation of ossification, regulation of spindle microtubule and centromere attachment, cytoskeleton tissue of cortical actin. According to GOcc analysis, they are mainly concentrated in plasma membrane part, cell junction, plasma membrane region and anterior membrane. According to GOmf analysis, they are mainly enriched in protein homodimerization activity, proximal promoter sequence-specific DNA binding and sulfur compound binding. KEGG showed that target genes were mainly enriched in Hippo signal pathway, p53 signal pathway and cancer pathway. KIFC2, TUBG1, RACGAP1, CHMP4C, SFN and MYH11 were identified as core genes. Gene expression heat map showed that KNTC1, MCM2, CKAP2, RACGAP1, CCNB1 were highly expressed in gallbladder carcinoma samples. CTD analysis showed that KNTC1, MCM2, CKAP2, RACGAP1, CCNB1 were associated with head and neck squamous cell carcinoma, necrosis, inflammation and hepatomegaly. CONCLUSIONS: KNTC1 and MCM2 are highly expressed in gallbladder cancer. Higher expression level correlates with worse prognosis.

Calcyclin-binding protein contributes to cholangiocarcinoma progression by inhibiting ubiquitination of MCM2.

Background: Cholangiocarcinoma (CCA) represents the epithelial cell cancer with high aggressiveness whose five-year survival rate is poor with standard treatment. Calcyclin-binding protein (CACYBP) shows aberrant expression within several malignant tumors, but the role of CACYBP in CCA remains unknown. Methods: Immunohistochemical (IHC) analysis was used to identify CACYBP overexpression in clinical samples of CCA patients. Moreover, its correlation with clinical outcome was revealed. Furthermore, CACYBP's effect on CCA cell growth and invasion was investigated in vitro and in vivo using loss-of-function experiments. Results: CACYBP showed up-regulation in CCA, which predicts the dismal prognostic outcome. CACYBP had an important effect on in-vitro and in-vivo cancer cell proliferation and migration. Additionally, knockdown of CACYBP weakened protein stability by promoting ubiquitination of MCM2. Accordingly, MCM2 up-regulation partly reversed CACYBP deficiency's inhibition against cancer cell viability and invasion. Thus, MCM2 might drive CCA development by Wnt/ß-catenin pathway. Conclusions: CACYBP exerted a tumor-promoting role in CCA by suppressing ubiquitination of MCM2 and activating Wnt/ß-catenin pathway, hence revealing that it may be the possible therapeutic target for CCA treatment.

Circ_0104700 contributes to acute myeloid leukemia progression by enhancing MCM2 expression through targeting miR-665.

OBJECTIVE: Acute myeloid leukemia (AML) is a common blood cancer associated with poor prognosis and high mortality. In this study, we investigated the role and underlying mechanism of action of circ_0104700 in the pathogenesis of AML. METHODS: Circ_0104700 was screened from the GEO database and detected in AML samples and cell lines. The effect of circ_0104700 on AML was analyzed using a methylcellulose colony assay, CCK-8 assay, and cell cycle and apoptosis analyses. The mechanism was explored using bioinformatic analysis, quantitative reverse transcription-PCR, dual-luciferase reporter assays, northern blotting and western blot analysis in AML cells. RESULTS: Circ_0104700 expression was higher in AML patients and AML cell lines. Functionally, circ_0104700 depletion attenuated cell viability and induced apoptosis in MV-4-11 and Kasumi-1 cells. Circ_0104700 depletion enhanced the G0/G1-phase proportion but reduced the proportion of S-phase cells in MV-4-11 and Kasumi-1 cells. circ_0104700 served as a competing endogenous RNA of miR-665 and enhanced MCM2 expression by sponging miR-665 in MV-4-11 and Kasumi-1 cells. Silencing circ_0104700 repressed the proliferation and cell cycle and induced apoptosis of MV-4-11 and Kasumi-1 cells by inhibiting miR-665. MCM2 depletion alleviated the proliferation and cell cycle and enhanced the apoptosis of MV-4-11 and Kasumi-1 cells by inactivating JAK/STAT signaling. JAK/STAT signaling was involved in circ_0104700-mediated malignant phenotypes of MV-4-11 and Kasumi-1 cells. CONCLUSION: circ_0104700 contributed to AML progression by enhancing MCM2 expression by targeting miR-665. Our findings provide novel potential therapeutic targets for AML, including circ_0104700, miR-665, and MCM2.

ESRG is critical to maintain the cell survival and self-renewal/pluripotency of hPSCs by collaborating with MCM2 to suppress p53 pathway.

The mechanisms of self-renewal and pluripotency maintenance of human pluripotent stem cells (hPSCs) have not been fully elucidated, especially for the role of those poorly characterized long noncoding RNAs (lncRNAs). ESRG is a lncRNA highly expressed in hPSCs, and its functional roles are being extensively explored in the field. Here, we identified that the transcription of ESRG can be directly regulated by OCT4, a key self-renewal factor in hPSCs. Knockdown of ESRG induces hPSC differentiation, cell cycle arrest, and apoptosis. ESRG binds to MCM2, a replication-licensing factor, to sustain its steady-state level and nuclear location, safeguarding error-free DNA replication. Further study showed that ESRG knockdown leads to MCM2 abnormalities, resulting in DNA damage and activation of the p53 pathway, ultimately impairs hPSC self-renewal and pluripotency, and induces cell apoptosis. In summary, our study suggests that ESRG, as a novel target of OCT4, plays an essential role in maintaining the cell survival and self-renewal/pluripotency of hPSCs in collaboration with MCM2 to suppress p53 signaling. These findings provide critical insights into the mechanisms underlying the maintenance of self-renewal and pluripotency in hPSCs by lncRNAs.

The importance of nuclear RAGE-Mcm2 axis in diabetes or cancer-associated replication stress.

An elevated frequency of DNA replication defects is associated with diabetes and cancer. However, data linking these nuclear perturbations to the onset or progression of organ complications remained unexplored. Here, we report that RAGE (Receptor for Advanced Glycated Endproducts), previously believed to be an extracellular receptor, upon metabolic stress localizes to the damaged forks. There it interacts and stabilizes the minichromosome-maintenance (Mcm2-7) complex. Accordingly, RAGE deficiency leads to slowed fork progression, premature fork collapse, hypersensitivity to replication stress agents and reduction of viability, which was reversed by the reconstitution of RAGE. This was marked by the 53BP1/OPT-domain expression and the presence of micronuclei, premature loss-of-ciliated zones, increased incidences of tubular-karyomegaly, and finally, interstitial fibrosis. More importantly, the RAGE-Mcm2 axis was selectively compromised in cells expressing micronuclei in human biopsies and mouse models of diabetic nephropathy and cancer. Thus, the functional RAGE-Mcm2/7 axis is critical in handling replication stress in vitro and human disease.

Different expression of DNMT1, PCNA, MCM2, CDT1, EZH2, GMNN and EP300 genes in lymphomagenesis of low vs. high grade lymphoma.

Tumour cells develop by accumulating changes in the genome that result in changes of main cellular processes. Aberrations of basic processes such as replication and chromatin reassembly are particularly important for genomic (in)stability. The aim of this study was to analyse the expression of genes whose products are crucial for the regulation of replication and chromatin reassembly during lymphomagenesis (DNMT1, PCNA, MCM2, CDT1, EZH2, GMNN, EP300). Non-tumour B cells were used as a control, and follicular lymphoma (FL) and the two most common groups of diffuse large B cell lymphoma (DLBCL) samples were used as a model for tumour progression. The results showed that there are significant changes in the expression of the analysed genes in lymphomagenesis, but also that these changes do not display linearity when assessed in relation to the degree of tumour aggression. Additionally, an integrated bioinformatics analysis of the difference in the expression of selected genes between tumour and non-tumour samples, and between tumour samples (FL vs. DLBCL) in five GEO datasets, did not show a consistent pattern of difference among the datasets.

MCM2 in human cancer: functions, mechanisms, and clinical significance.

BACKGROUND: Aberrant DNA replication is the main source of genomic instability that leads to tumorigenesis and progression. MCM2, a core subunit of eukaryotic helicase, plays a vital role in DNA replication. The dysfunction of MCM2 results in the occurrence and progression of multiple cancers through impairing DNA replication and cell proliferation. CONCLUSIONS: MCM2 is a vital regulator in DNA replication. The overexpression of MCM2 was detected in multiple types of cancers, and the dysfunction of MCM2 was correlated with the progression and poor prognoses of malignant tumors. According to the altered expression of MCM2 and its correlation with clinicopathological features of cancer patients, MCM2 was thought to be a sensitive biomarker for cancer diagnosis, prognosis, and chemotherapy response. The anti-tumor effect induced by MCM2 inhibition implies the potential of MCM2 to be a novel therapeutic target for cancer treatment. Since DNA replication stress, which may stimulate anti-tumor immunity, frequently occurs in MCM2 deficient cells, it also proposes the possibility that MCM2 targeting improves the effect of tumor immunotherapy.

Comparative evaluation of immunohistochemical expression of MCM2 and Ki67 in oral epithelial dysplasia and oral squamous cell carcinoma.

Aim and Objectives: The aim and objective of the study were to evaluate the immunohistochemical expression of proliferative markers, Ki67, and MCM2 in oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC), to compare the relationship of their staining patterns, and to look for correlation between them, if any. Materials and Methods: Thirty archival paraffin-embedded tissue blocks of previously diagnosed cases of OED, OSCC each, and 10 normal oral mucosa were used in the study. Immunohistochemical staining for MCM2 and Ki67 markers was done and the slides were individually evaluated for MCM2 and Ki67 expression, with immunopositivity determined on the basis of dark brown staining of the nucleus. The number of positively stained nuclei was counted in 10 representative areas and the data were charted and statistically analyzed. Results: The overall mean expression of both the proteins increased progressively from normal mucosa to OED to OSCC. In normal mucosa, all positively stained nuclei were seen in the basal compartment of the epithelium, while in dysplastic cases, expression was seen toward the surface of squamous epithelium. In OSCC, the frequency of expression of MCM2 and Ki-67 proteins showed an inverse correlation with the degree of tumor differentiation. In well-differentiated cases, the positivity of either marker was restricted to the outermost layer of the tumor cells. In moderately differentiated cases, an expression of Ki-67 was more diffuse in inner layers, whereas the MCM2 antigen was found to be more intense and diffuse in both the inner and outer layers. Whereas in poorly differentiated SCC, positive expression was seen in most of the tumor cells, the mean expression of MCM2 was found to be higher than that of Ki67 in all cases. Conclusion: MCM2, as a proliferation marker, is superior to Ki67 as it indicates the capacity of proliferation and the ability of DNA replication of a cell.

Mcm2 hypomorph leads to acute leukemia or hematopoietic stem cell failure, dependent on genetic context.

Minichromosome maintenance proteins (Mcm2-7) form a hexameric complex that unwinds DNA ahead of a replicative fork. The deficiency of Mcm proteins leads to replicative stress and consequent genomic instability. Mice with a germline insertion of a Cre cassette into the 3'UTR of the Mcm2 gene (designated Mcm2Cre ) have decreased Mcm2 expression and invariably develop precursor T-cell lymphoblastic leukemia/lymphoma (pre-T LBL), due to 100-1000 kb deletions involving important tumor suppressor genes. To determine whether mice that were protected from pre-T LBL would develop non-T-cell malignancies, we used two approaches. Mice engrafted with Mcm2Cre/Cre Lin- Sca-1+ Kit+ hematopoietic stem/progenitor cells did not develop hematologic malignancy; however, these mice died of hematopoietic stem cell failure by 6 months of age. Placing the Mcm2Cre allele onto an athymic nu/nu background completely prevented pre-T LBL and extended survival of these mice three-fold (median 296.5 vs. 80.5 days). Ultimately, most Mcm2Cre/Cre ;nu/nu mice developed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We identified recurrent deletions of 100-1000 kb that involved genes known or suspected to be involved in BCP-ALL, including Pax5, Nf1, Ikzf3, and Bcor. Moreover, whole-exome sequencing identified recurrent mutations of genes known to be involved in BCP-ALL progression, such as Jak1/Jak3, Ptpn11, and Kras. These findings demonstrate that an Mcm2Cre/Cre hypomorph can induce hematopoietic dysfunction via hematopoietic stem cell failure as well as a "deletor" phenotype affecting known or suspected tumor suppressor genes.

ITRAQ-based quantitative proteomic analysis reveals that VPS35 promotes the expression of MCM2-7 genes in HeLa cells.

Vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex that regulates endosomal trafficking in eukaryotic cells. Recent studies have shown that VPS35 promotes tumor cell proliferation and affects the nuclear accumulation of its interacting partner. In this study, isobaric tags for relative and absolute quantitation (iTRAQ)-based mass spectrometry were used to measure the changes in nuclear protein abundance in VPS35-depleted HeLa cells. A total of 47 differentially expressed proteins were identified, including 27 downregulated and 20 upregulated proteins. Gene ontology (GO) analysis showed that the downregulated proteins included several minichromosome maintenance (MCM) proteins described as cell proliferation markers, and these proteins were present in the MCM2-7 complex, which is essential for DNA replication. Moreover, we validated that loss of VPS35 reduced the mRNA and protein expression of MCM2-7 genes. Notably, re-expression of VPS35 in VPS35 knockout HeLa cells rescued the expression of these genes. Functionally, we showed that VPS35 contributes to cell proliferation and maintenance of genomic stability of HeLa cells. Therefore, these findings reveal that VPS35 is involved in the regulation of MCM2-7 gene expression and establish a link between VPS35 and cell proliferation.

Expression of MCM2 as a Proliferative Marker in Actinic Keratosis and Cutaneous Squamous Cell Carcinoma.

BACKGROUND/AIM: Minichromosome maintenance protein 2 (MCM2) can be considered an indicator of cancer clinical outcome. In this study, we tried to estimate the usefulness of assessing MCM2 protein expression in actinic keratosis (AK) and cutaneous squamous cell carcinoma (cSCC). MATERIALS AND METHODS: The study included 22 lesions of AK, 57 of cSCC and 17 tissue samples of the healthy skin. RESULTS: Higher average expression of MCM2 protein in cSCC and AK was demonstrated in comparison to healthy skin (p=0.01). Likewise, the level of MCM2 expression differed statistically significantly (p=0.02) between SCC, AK, and healthy skin. Significant correlations between MCM2 expression and Ki-67 and p53 antigen were found (r=0.51, p=0.01; r=0.45, p=0.04 respectively) in AK lesions, however these relationships were not noted in cSCC. CONCLUSION: MCM2 is overexpressed in both AK and cSCC lesions, however this protein cannot be considered an important indicator of proliferation in cSCC.

MCMBP promotes the assembly of the MCM2-7 hetero-hexamer to ensure robust DNA replication in human cells.

The MCM2-7 hetero-hexamer is the replicative DNA helicase that plays a central role in eukaryotic DNA replication. In proliferating cells, the expression level of the MCM2-7 hexamer is kept high, which safeguards the integrity of the genome. However, how the MCM2-7 hexamer is assembled in living cells remains unknown. Here, we revealed that the MCM-binding protein (MCMBP) plays a critical role in the assembly of this hexamer in human cells. MCMBP associates with MCM3 which is essential for maintaining the level of the MCM2-7 hexamer. Acute depletion of MCMBP demonstrated that it contributes to MCM2-7 assembly using nascent MCM3. Cells depleted of MCMBP gradually ceased to proliferate because of reduced replication licensing. Under this condition, p53-positive cells exhibited arrest in the G1 phase, whereas p53-null cells entered the S phase and lost their viability because of the accumulation of DNA damage, suggesting that MCMBP is a potential target for killing p53-deficient cancers.