Affinage

MCM3

DNA replication licensing factor MCM3 · UniProt P25205

Length
808 aa
Mass
91.0 kDa
Annotated
2026-06-10
82 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MCM3 is an essential subunit of the heterohexameric MCM2-7 replicative DNA helicase and a core component of the replication licensing system that restricts genome duplication to a single round per cell cycle (PMID:7758114, PMID:7760938). It exhibits cell-cycle-regulated nuclear accumulation and chromatin association, entering the nucleus at the end of mitosis, persisting through G1, and dissociating at the onset of S phase, a loss that prevents re-initiation at origins (PMID:8224843, PMID:7925275). Stable MCM complex accumulation requires phosphorylation-driven assembly: CDK1-dependent phosphorylation of Ser-112 triggers MCM3 assembly with the other MCM subunits and chromatin loading, and loss of MCM3 destabilizes the remaining MCM proteins (PMID:18524952). Within the MCM2-7 ring, MCM3 contributes catalytically through its pre-sensor 1 hairpin lysine, which is specifically required for DNA unwinding, and architecturally through its winged helix domain, which docks on MCM2 to form a 'safety latch' that blocks DNA entry into the central channel until ORC-CDC6 opens the gate [PMID:24349215, PMID:bio_10.1101_2025.05.31.656953]. MCM3 chromatin loading and S-phase timing are tuned by a network of modifications—Chk1 phosphorylation at Ser-205 restrains replication fork progression, cyclin E/CDK2 phosphorylation at Thr-722 promotes chromatin binding and S-phase checkpoint control, and ATM/ATR phosphorylation of C-terminal DSQ motifs links the soluble pool to DNA-damage signaling (PMID:21965652, PMID:25809478, PMID:17244605). Its chromatin association is further modulated by MCM3AP-mediated acetylation, which inhibits replication initiation but not elongation (PMID:11258703, PMID:12226073), and by nuclear import controlled by an MCM3 NLS (PMID:9712829, PMID:39836669). Beyond replication, MCM3 is selectively cleaved by caspases during apoptosis (PMID:9473350), is ubiquitylated by the KEAP1-CUL3-RBX1 E3 ligase and deubiquitylated by USP1 (PMID:27621311, PMID:41797940), and competes with NRF2 for KEAP1 binding to modulate antioxidant signaling (PMID:30108253, PMID:41797940). Biallelic pathogenic MCM3 variants disrupt MCM complex formation and impair S-phase progression in patient-derived cells (PMID:33654309).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1991 High

    Established that MCM2 and MCM3 are functionally interdependent partners in DNA replication initiation rather than acting alone, the first hint of an MCM complex.

    Evidence Genetic epistasis, synthetic lethality, and bidirectional overexpression in S. cerevisiae

    PMID:2044961

    Open questions at the time
    • Did not define a physical complex or biochemical activity
    • No molecular mechanism of interaction
  2. 1993 High

    Answered how MCM proteins enforce once-per-cycle replication, linking cell-cycle-regulated nuclear/chromatin localization of MCM3 to prevention of origin reinitiation.

    Evidence 2D gel analysis of origin firing, nuclear fractionation, immunofluorescence, minichromosome stability in yeast

    PMID:8224843

    Open questions at the time
    • Mechanism driving chromatin dissociation not defined
    • Did not identify the regulatory modification
  3. 1995 High

    Defined MCM3 as a replication licensing factor that binds chromatin before nuclear formation and dissociates during replication, and that the MCM2/3/5 complex licenses G2 but not already-licensed G1 chromatin, resolving licensing into discrete loading stages.

    Evidence Immunodepletion and reconstitution in Xenopus egg extracts, sperm/HeLa nuclei replication assays, co-IP of MCM3 with MCM5

    PMID:7610039 PMID:7758114 PMID:7760938 PMID:8574584

    Open questions at the time
    • Identity of the cytosolic loading factor unresolved
    • Helicase activity not yet demonstrated
  4. 1998 Medium

    Identified Map80 as an MCM3-interacting partner that promotes nuclear import via the MCM3 NLS, and showed MCM3 is selectively destroyed by caspases in apoptosis, coupling replication licensing to cell-fate decisions.

    Evidence Yeast two-hybrid, co-IP, NLS mutagenesis, recombinant import assays; apoptosis models with caspase inhibitors and family-member controls

    PMID:9473350 PMID:9633535 PMID:9712829

    Open questions at the time
    • Caspase cleavage sites not mapped
    • Functional consequence of Map80 import for replication not quantified
  5. 2001 High

    Showed that acetylation is a direct regulatory input on MCM3, with MCM3AP acetylating chromatin-bound MCM3 to inhibit replication initiation but not elongation.

    Evidence Yeast two-hybrid, in vitro acetyltransferase assays, GNAT-motif mutagenesis, Xenopus cell-free initiation vs elongation assays, chromatin fractionation

    PMID:11258703 PMID:12226073

    Open questions at the time
    • Acetylated residues on MCM3 not mapped
    • How acetylation blocks initiation mechanistically unresolved
  6. 2002 Medium

    Dissected how MCM3 mutations and ubiquitination affect distinct steps of complex assembly versus origin recruitment, refining where MCM3 acts in the licensing pathway.

    Evidence Allele characterization (mcm3-10 P118L, mcm3-1 G246E), co-IP, ChIP at origins, ubiquitination and uba1-165 suppressor analysis in yeast

    PMID:12060653 PMID:12200430

    Open questions at the time
    • E3 ligase mediating assembly-stage ubiquitination not identified
    • Ubiquitin linkage type undefined
  7. 2008 High

    Established phosphorylation as the trigger for MCM complex assembly, showing CDK1 phosphorylation of Ser-112 drives MCM3 assembly and chromatin loading and is required for stability of the other MCM subunits.

    Evidence In vitro kinase assays, phosphosite mutagenesis, co-IP, chromatin fractionation, siRNA in mammalian cells

    PMID:18524952

    Open questions at the time
    • Roles of Ser-611/Thr-719 phosphorylation not resolved
    • Structural basis of phospho-dependent assembly unknown
  8. 2011 High

    Connected MCM3 phosphorylation to checkpoint control, showing cyclin E/CDK2 phosphorylation of Thr-722 governs chromatin loading and modulates S-phase entry and CHK1 activation.

    Evidence In vitro kinase assay, T722A mutagenesis, chromatin fractionation, FACS, western blotting

    PMID:21965652

    Open questions at the time
    • Direct link between Thr-722 and CHK1 pathway mechanistically indirect
    • In vivo kinase specificity not isolated
  9. 2015 High

    Revealed that MCM3 phosphorylation by Chk1 at Ser-205 negatively tunes normal replication fork progression and is reversed under replicative stress, integrating MCM3 into checkpoint signaling.

    Evidence In vitro Chk1 kinase assay, S205A mutagenesis, DNA fiber assay, FACS, replicative-stress treatment

    PMID:25809478

    Open questions at the time
    • How Ser-205 phosphorylation slows fork progression mechanistically unknown
    • Phosphatase reversing Ser-205 not defined here
  10. 2007 High

    Showed ATM/ATR phosphorylate MCM3 C-terminal DSQ motifs (Ser-725/Ser-732), with the modified form enriched in the soluble pool, linking the non-chromatin MCM3 fraction to DNA-damage signaling.

    Evidence Phosphospecific antibodies, in vitro ATM kinase assay, chromatin fractionation, UV/IR damage treatment

    PMID:17244605

    Open questions at the time
    • Downstream consequence of C-terminal phosphorylation unresolved
    • Whether modification affects helicase activity unknown
  11. 2013 High

    Provided direct catalytic evidence that MCM3 contributes to unwinding, showing its pre-sensor 1 hairpin lysine (K499) is required for MCM2-7 helicase activity.

    Evidence Reconstituted MCM2-7 helicase and ATPase assays, EMSA, viability and synthetic lethality in yeast

    PMID:24349215

    Open questions at the time
    • Structural mechanism of PS1 hairpin in DNA translocation not resolved
    • Coupling to other subunits' motors undefined
  12. 2018 Medium

    Expanded MCM3 regulation to prolyl isomerization, autoinhibitory loading control, NRF2 signaling, and CDK-coupled nuclear degradation, broadening its mechanistic and signaling roles.

    Evidence Pin1 WW-domain co-IP/mutagenesis; MCM3-C peptide competition in Xenopus extracts with ATP-γ-S; KEAP1/NRF2 competition binding; CDK phosphodegron/SCF analysis in yeast

    PMID:29261034 PMID:30108253 PMID:30316783 PMID:30376991

    Open questions at the time
    • Physiological significance of MCM3-C autoinhibition in vivo unresolved
    • Interplay between licensing and NRF2 competition unclear
  13. 2016 High

    Defined the KEAP1-CUL3-RBX1 complex as an MCM3 E3 ligase that ubiquitylates surface residues without changing total MCM3 levels, instead co-cycling with MCM2-7 on chromatin.

    Evidence Affinity proteomics, in vitro ubiquitylation, ubiquitin remnant MS site mapping, cell-cycle chromatin fractionation

    PMID:27621311

    Open questions at the time
    • Functional outcome of MCM3 ubiquitylation on helicase dynamics unresolved
    • Deubiquitylase not identified in this study
  14. 2019 Medium

    Identified PLK1 as an additional Ser-112 kinase whose MCM3 phosphorylation promotes proliferation and suppresses apoptosis in renal cell carcinoma, linking MCM3 modification to tumor growth.

    Evidence Phos-tag SDS-PAGE, immunofluorescence, PLK1/MCM3 perturbation, xenograft mouse model

    PMID:31186514

    Open questions at the time
    • Relationship between CDK1 and PLK1 inputs to Ser-112 unresolved
    • Direct kinase-substrate biochemistry limited
  15. 2021 Medium

    Established a human disease link, showing biallelic MCM3 variants impair MCM complex formation and S-phase progression in patient cells.

    Evidence Exome/genome sequencing and functional studies in patient-derived cells

    PMID:33654309

    Open questions at the time
    • Specific molecular defect of variants not structurally resolved
    • Genotype-phenotype spectrum limited to single study
  16. 2023 Medium

    Showed a lncRNA scaffold (LINK-A) couples MCM3 to CDK1 and HIF-1α, linking MCM3 phosphorylation/loading to cell-cycle progression and metabolic reprogramming.

    Evidence Co-IP of MCM3-CDK1 and MCM3-HIF-1α, LINK-A perturbation, chromatin loading, FACS, HIF-1α target expression

    PMID:37858471

    Open questions at the time
    • Direct vs scaffolded nature of MCM3-HIF-1α interaction unclear
    • Single-lab co-IP evidence without reciprocal structural validation
  17. 2025 Medium

    Resolved the structural basis of replication safety, showing the MCM3 winged helix domain docks on MCM2 as a DNA-entry 'safety latch' opened by ORC-CDC6, and that latch-disrupting mutations cause replication defects.

    Evidence Cryo-EM of DNA-free human MCM2-7 (preprint), WHD-MCM2 interface mutagenesis, replication and checkpoint reporter assays; NLS-importin modeling and functional assays in yeast

    PMID:39836669 PMID:bio_10.1101_2025.05.31.656953

    Open questions at the time
    • Cryo-EM findings from a preprint not yet peer-reviewed
    • Dynamics of latch opening during origin firing not directly visualized
  18. 2026 Medium

    Identified USP1 as the deubiquitinase that stabilizes MCM3 by removing K48-linked chains, with excess MCM3 sequestering KEAP1 to activate NRF2 and modulate mitophagy in hepatocellular carcinoma.

    Evidence Co-IP, K48-linkage-specific western blotting, KEAP1-NRF2 interaction assays, MCM3 knockdown with mitophagy/NRF2 readouts, xenograft model

    PMID:41797940

    Open questions at the time
    • Balance between KEAP1-CUL3 ubiquitylation and USP1 removal not quantified
    • Whether NRF2 modulation depends on chromatin-free MCM3 pool unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse MCM3 post-translational modifications, the WHD safety latch, and moonlighting KEAP1/NRF2 functions are mechanistically integrated during a single replication cycle remains unresolved.
  • No unified model linking phosphorylation/acetylation/ubiquitylation to latch opening
  • Stoichiometry and timing of competing modifications undefined
  • In vivo significance of NRF2 competition relative to replication role unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0005198 structural molecule activity 2 GO:0140657 ATP-dependent activity 2 GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0005634 nucleus 5 GO:0000228 nuclear chromosome 4 GO:0005654 nucleoplasm 2 GO:0005829 cytosol 2
Pathway
R-HSA-69306 DNA Replication 4 R-HSA-1640170 Cell Cycle 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-5357801 Programmed Cell Death 1
Partners
CDK1GANPKEAP1MCM2MCM3APMCM5PIN1USP1
Complex memberships
MCM2-7 helicase

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Xenopus MCM3 (a 100 kDa protein) is a component of the replication licensing factor; it binds to sperm chromatin before nuclear formation and dissociates from nuclear DNA during replication progression without being transported into nuclei, consistent with a role in restricting replication to once per cell cycle. Immunodepletion from Xenopus egg extracts, binding assays with sperm chromatin, cDNA cloning, cell-cycle immunofluorescence in HeLa cells Cell High 7758114
1995 Immunodepletion of a complex containing XMCM3 (along with MCM2 and MCM5 homologues) from Xenopus egg extracts inhibits replication of sperm nuclei or permeable G2 HeLa nuclei, but not G1 HeLa nuclei, demonstrating that the MCM2/3/5 complex is required for replication licensing of G2 but not already-licensed G1 chromatin. Immunodepletion from Xenopus egg extracts, replication assay with sperm nuclei and permeable HeLa nuclei Nature High 7760938
1995 The nuclear envelope does not prevent entry of XMCM3 into the nucleus but does prevent its binding to chromatin. A cytosolic 'loading factor' excluded by the nuclear membrane is required for MCM3 to bind chromatin; resolving replication licensing into two stages: loading-factor entry and subsequent MCM3 chromatin binding. Xenopus egg extract cell-free system; intact vs. permeabilized nuclear envelope experiments; chromatin-binding assays; immunofluorescence Current biology : CB High 8574584
1993 Yeast MCM2 and MCM3 proteins show cell-cycle-regulated nuclear localization: they enter the nucleus at the end of mitosis, persist through G1, and disappear at the onset of S phase. A fraction becomes tightly chromatin-associated, and this disappearance prevents reinitiation of DNA synthesis at replication origins. Two-dimensional gel electrophoresis of replication origins, immunofluorescence cell-cycle fractionation, minichromosome stability assays in S. cerevisiae Genes & development High 8224843
1994 Murine MCM3 (P1 protein) exists in the nucleus in an underphosphorylated form associated with a particular nuclear structure and a hyperphosphorylated form loosely bound to the nucleus. During S phase, the underphosphorylated form disappears first from euchromatic then heterochromatic regions, in parallel with temporal DNA replication order, suggesting that phosphorylation-dependent dissociation prevents re-replication. Polyclonal antibody immunofluorescence, nuclear fractionation, pulse-chase labeling, cell-cycle staging of mouse cell line The EMBO journal High 7925275
1991 MCM2 and MCM3 in S. cerevisiae play interacting roles in DNA replication initiation: double mutants of mcm2-1 and mcm3-1 are inviable at permissive temperature; overproduction of Mcm3 accentuates the mcm2-1 defect, while overproduction of Mcm2 partially complements mcm3-1, demonstrating genetic interaction and functional interdependence. Genetic epistasis, synthetic lethality analysis, overexpression complementation in S. cerevisiae Genes & development High 2044961
2001 MCM3AP (MCM3-associated protein) is an acetyltransferase that directly acetylates MCM3 in vitro and in vivo. Chromatin-bound MCM3 is acetylated in vivo, and MCM3AP is also chromatin-bound. MCM3AP contains GCN5-related N-acetyltransferase (GNAT) superfamily acetyl-CoA binding motifs; mutation of these motifs significantly inhibits acetyltransferase activity. Overexpression of MCM3AP inhibits DNA replication, and mutation of the acetylase motifs abolishes this inhibitory effect. Yeast two-hybrid screen, in vitro acetyltransferase assay, site-directed mutagenesis of acetyl-CoA binding motifs, overexpression DNA replication assay, chromatin fractionation EMBO reports High 11258703
2002 MCM3AP (MCM3 acetylase) inhibits initiation but not elongation of DNA replication. Both wild-type and acetylase-deficient MCM3AP bind chromatin via interaction with MCM3, but only wild-type (acetyltransferase-active) MCM3AP inhibits initiation, indicating that acetylase activity—not chromatin binding alone—is required for inhibition. Interaction with MCM3 is essential for nuclear localization and chromatin binding of MCM3AP. Cell-free Xenopus replication system; comparison of initiation vs. elongation; wild-type vs. acetyltransferase-deficient MCM3AP mutant; chromatin binding assays The Journal of biological chemistry High 12226073
2016 KEAP1 ubiquitylates MCM3 via the KEAP1-CUL3-RBX1 E3 ligase complex both in cells and in vitro. Ubiquitylation sites were mapped by ubiquitin remnant profiling to predicted surface-exposed residues of the MCM2-7 complex. However, KEAP1 does not regulate total MCM3 protein stability or subcellular localization; instead, KEAP1 associates with chromatin in a cell-cycle-dependent manner with kinetics similar to MCM2-7, suggesting it affects MCM2-7 dynamics or function. Parallel affinity capture proteomics, in vitro ubiquitylation assay, ubiquitin remnant profiling mass spectrometry, cell cycle chromatin fractionation, immunoprecipitation The Journal of biological chemistry High 27621311
2008 CDK1 phosphorylates MCM3 at Ser-112, Ser-611, and Thr-719. In vivo, CDK1-dependent phosphorylation of Ser-112 triggers MCM3 assembly with the remaining MCM subunits and subsequent chromatin loading. Loss of MCM3 destabilizes other MCM proteins, indicating that phosphorylation-dependent assembly is essential for stable MCM complex accumulation. In vitro kinase assay, phosphosite mutagenesis, co-immunoprecipitation, chromatin fractionation, siRNA knockdown in mammalian cells Proceedings of the National Academy of Sciences of the United States of America High 18524952
2011 Cyclin E/Cdk2 phosphorylates MCM3 at Thr-722. The MCM3 T722A mutant binds chromatin much less efficiently than wild-type MCM3. Overexpression of wild-type MCM3 (but not T722A) inhibits S phase entry and upregulates phosphorylation of CHK1(Ser-345) and CDK2(Thr-14), implicating this phosphorylation event in S phase checkpoint control in addition to chromatin loading. In vitro kinase assay with cyclin E/Cdk2, phosphosite mutagenesis (T722A), chromatin fractionation, cell-cycle FACS analysis, western blotting The Journal of biological chemistry High 21965652
2015 Chk1 phosphorylates MCM3 at Ser-205 under normal growth conditions. The S205A mutation increases DNA replication track length and shortens S phase, demonstrating that Ser-205 phosphorylation negatively regulates normal DNA replication. Upon replicative stress, this inhibitory phosphorylation is reduced, coinciding with ssDNA generation and ATR activation, linking MCM3 phosphorylation to checkpoint activation. In vitro Chk1 kinase assay, phosphosite mutagenesis (S205A), DNA fiber assay (replication track length), FACS cell-cycle analysis, immunoprecipitation, replicative-stress treatment The Journal of biological chemistry High 25809478
2007 ATM phosphorylates MCM3 at tandem DSQ motifs (Ser-725 and Ser-732) in vitro and in vivo. ATR also contributes to UV-induced MCM3 phosphorylation. The ATM-phosphorylated form of MCM3 is preferentially localized to the soluble nucleoplasmic fraction rather than chromatin-bound, suggesting that chromatin-loaded MCM3 C-terminus is sequestered from ATM-dependent checkpoint signals. Phosphospecific antibody purification, in vitro ATM kinase assay, chromatin fractionation, DNA damage treatment (UV, IR), immunoprecipitation The Journal of biological chemistry High 17244605
1998 MCM3 is selectively cleaved early in multiple models of apoptosis (but other MCM family members are not). Cleavage is prevented by caspase inhibitors and does not occur during necrosis induced by energy deprivation, identifying caspase-dependent proteolysis of MCM3 as a specific apoptotic event that inactivates the MCM complex. Multiple apoptosis models, caspase inhibitor experiments, western blotting for MCM3 and other MCM family members, necrosis controls Experimental cell research High 9473350
1998 Map80 (an 80 kDa protein) was identified as an MCM3-associated protein by two-hybrid screen and confirmed by co-immunoprecipitation. Map80 facilitates nuclear localization of MCM3: a nuclear localization signal (NLS) in MCM3 was identified, and mutagenesis of the NLS abolished Map80 binding; addition of recombinant Map80 increased nuclear MCM3. Yeast two-hybrid screen, co-immunoprecipitation, NLS mutagenesis, recombinant protein addition assay, nuclear localization quantification The Journal of biological chemistry Medium 9712829
1995 Mouse MCM3 (P1) physically interacts with CDC46 (MCM5 homologue), as demonstrated by immunochemical co-precipitation, indicating that MCM proteins function coordinately in DNA replication. Co-immunoprecipitation from mouse cell extracts Nucleic acids research Medium 7610039
2002 A fraction of Mcm3 is polyubiquitinated at the onset of MCM complex assembly during mitosis. Reducing ubiquitination via the uba1-165 mutation (a suppressor of mcm3-10) restores interaction of Mcm3-10 with other MCM subunits and its recruitment to replication origins, suggesting ubiquitination regulates MCM complex assembly. Ubiquitination assay, genetic suppressor analysis (uba1-165), co-immunoprecipitation, chromatin immunoprecipitation at replication origins in S. cerevisiae The Journal of biological chemistry Medium 12200430
2002 Mcm3-10 (P118L substitution) compromises interaction with Mcm5 and prevents recruitment of Mcm3 and Mcm7 to replication origins. Mcm3-1 (G246E) does not disrupt Mcm5 interaction or MCM complex origin recruitment but reduces replication initiation efficiency, indicating these two mutations affect distinct steps: Mcm3-10 acts before, and Mcm3-1 after, MCM2-7 complex recruitment to origins. Allele characterization, co-immunoprecipitation of Mcm3-Mcm5 interaction, chromatin immunoprecipitation at replication origins in S. cerevisiae The Journal of biological chemistry Medium 12060653
2013 The conserved lysine in the pre-sensor 1 (PS1) hairpin of Mcm3 (K499) is essential for viability in S. cerevisiae. Reconstituted MCM2-7 containing Mcm3(K499A) has severely decreased helicase activity in vitro, with altered ssDNA binding and subtle complex-association changes, but near-normal ATPase activity, demonstrating that the Mcm3 PS1 hairpin is specifically required for DNA unwinding. In vitro helicase assay with reconstituted MCM2-7 complex, ATPase assay, electrophoretic mobility shift assay (ssDNA binding), viability assays, synthetic lethality screen in S. cerevisiae PloS one High 24349215
1997 A nuclear localization sequence (NLS) in yeast Mcm3 is necessary for nuclear translocation and sufficient to direct beta-galactosidase to the nucleus. Cell-cycle-specific nuclear accumulation of Mcm3 is determined by nuclear retention or nuclear targeting, not regulated nuclear import through the NLS itself, since mutagenesis of four adjacent Cdc28 phosphorylation sites has no phenotypic effect on nuclear accumulation. NLS mutagenesis, beta-galactosidase fusion nuclear targeting assay, Cdc28 phosphorylation site mutagenesis, plasmid stability assays, cell growth assays in S. cerevisiae Genes to cells : devoted to molecular & cellular mechanisms Medium 9427284
1997 In S. cerevisiae, Mcm3 is a phosphoprotein that exists in multiple isoforms; only a small fraction tightly associates with chromatin from late M phase to beginning of S phase, with the majority distributed between cytoplasm and nucleoplasm throughout the cell cycle. Distinct phosphorylated isoforms of Mcm3 appear at specific cell-cycle stages, consistent with phosphorylation regulating MCM function. Cell-cycle synchronization, chromatin fractionation, 2D gel electrophoresis (isoform detection), western blotting in S. cerevisiae Molecular biology of the cell Medium 9285827
2019 PLK1 phosphorylates MCM3 on Ser-112 in a PLK1-dependent manner (demonstrated by Mn2+-Phos-tag SDS-PAGE, western blotting, and immunofluorescence). PLK1-mediated MCM3 phosphorylation promotes renal cell carcinoma cell cycle proliferation and suppresses apoptosis in vitro and in vivo. Mn2+-Phos-tag SDS-PAGE, western blotting, immunofluorescence, PLK1 overexpression/knockout, MCM3 overexpression/knockout, xenograft mouse model Cancer gene therapy Medium 31186514
2018 Pin1 (peptidyl-prolyl cis/trans isomerase) directly interacts with MCM3 via Pin1's WW domain. Proline-directed phosphorylation of MCM3 at S112 and T722 is required for Pin1 interaction. Pin1 coordinates phosphorylation-dependent loading of MCM3 onto chromatin and its unloading, mediating S phase control. Co-immunoprecipitation, domain mapping (WW domain), phosphosite mutagenesis (S112, T722), chromatin fractionation Journal of molecular biology Medium 30316783
2000 GANP (a 210 kDa nuclear protein) associates with MCM3 in B cells, demonstrated by co-immunoprecipitation, and contains a Map80-homologous domain capable of binding MCM3. Co-immunoprecipitation from B cell extracts, domain analysis Blood Low 10733502
2002 G5PR (a phosphatase regulatory subunit identified by yeast two-hybrid screening) associates with GANP in vivo and, via GANP, connects to MCM3. A G5PR-associated complex (including PP5 and PP2A phosphatases) has phosphatase activity toward MCM3 in vitro, suggesting a phosphatase complex can act on MCM3 to regulate its phosphorylation state. Yeast two-hybrid screen, co-immunoprecipitation, in vitro phosphatase assay on MCM3, cellular localization Genes to cells : devoted to molecular & cellular mechanisms Low 12167160
2018 MCM3 competes with NRF2 for binding to KEAP1, with the helix-2-insert motif of MCM3 structurally mimicking NRF2 KEAP1-binding determinants. This competition was demonstrated by reciprocal binding assays, showing that MCM3 can modulate KEAP1-controlled NRF2 activities. Competition binding assays, structural comparative analysis, mutagenesis of binding interface Scientific reports Medium 30108253
2018 CDK-mediated phosphorylation of Mcm3 in budding yeast regulates its nuclear localization and also promotes its SCF-proteasome-dependent degradation within the nucleus; CDK phosphorylation simultaneously excludes Mcm3 from the nucleus and generates a phosphodegron for nuclear degradation, thus negatively regulating nuclear MCM levels. Phosphorylation-site mutagenesis, nuclear fractionation, proteasome inhibitor experiments, SCF pathway genetic analysis in S. cerevisiae Biochemical and biophysical research communications Medium 30376991
2018 A C-terminal peptide of MCM3 (MCM3-C) prevents binding of loading factors ORC, Cdc6, and Cdt1 to DNA in Xenopus egg extracts independently of MCM loading, and MCM already loaded onto DNA similarly prevents loading factor binding; ATP-γ-S suppresses both inhibitory activities. This reveals a negative autoregulatory mechanism where loaded MCM3 C-terminus interferes with further MCM loading near licensed origins. Cell-free Xenopus egg extract MCM loading assay, peptide competition experiments, ATP analog (ATP-γ-S) inhibition, chromatin binding assays Cell cycle (Georgetown, Tex.) Medium 29261034
2025 The MCM3 winged helix domain (WHD) docks on MCM2 in both DNA-free double hexamer and single hexamer structures, creating a 'safety latch' across the DNA entry gate that blocks DNA entry into the central channel. This latch can be opened by ORC-CDC6 binding. Disease-related and designed mutations disrupting this latch cause replication defects and DNA damage checkpoint activation. Cryo-EM structural determination of DNA-free human MCM2-7, site-directed mutagenesis of WHD-MCM2 interface, replication defect assays, DNA damage checkpoint reporter assays bioRxivpreprint Medium bio_10.1101_2025.05.31.656953
2025 The nuclear localization sequence (NLS) of Mcm3 requires precise positioning of basic residues for optimal interaction with importin; disrupting these interactions (by mutagenesis guided by AlphaFold 3 modeling) impairs nuclear import of Mcm3, reduces chromatin loading of the MCM complex, and impairs cell growth. Mutagenesis of NLS residues, AlphaFold 3 structural modeling, nuclear import assays, chromatin fractionation, cell growth assays in S. cerevisiae PLoS genetics High 39836669
2021 Biallelic pathogenic variants in MCM3 are associated with disrupted MCM complex formation and impaired S phase progression, as demonstrated by functional studies in patient-derived cells, establishing MCM3 as required for efficient MCM2-7 complex assembly and S phase entry. Exome/genome sequencing, functional studies in patient-derived cells measuring MCM complex formation and S phase progression European journal of human genetics : EJHG Medium 33654309
2010 Human cytomegalovirus IE86 protein binds to cellular MCM3 (demonstrated by co-immunoprecipitation), but does not inhibit MCM3 binding to an EBV replication origin (oriP) or cellular DNA synthesis in U373MG cells. Co-immunoprecipitation, chromatin immunoprecipitation at EBV oriP, cellular DNA synthesis assay Acta virologica Low 20545442
1998 More than 60% of pulse-labeled MCM3 protein is degraded within 24 hours in HeLa cells, and MCM3 protein levels significantly decrease during HL60 cell differentiation in vitro and in the upper differentiating cell layers of human epidermis, indicating regulated MCM3 degradation upon initiation of differentiation. Pulse-chase metabolic labeling, western blotting during HL60 differentiation, immunohistochemistry on epidermal tissue sections Experimental cell research Medium 9633535
2023 LINK-A (long non-coding RNA) promotes interaction between MCM3 and CDK1, increasing MCM3 phosphorylation and facilitating MCM complex chromatin loading, thereby promoting cell-cycle progression. LINK-A also disrupts an interaction between MCM3 and HIF-1α, abrogating MCM3-mediated HIF-1α transcriptional repression and promoting glycolysis. Co-immunoprecipitation to detect MCM3-CDK1 and MCM3-HIF-1α interactions, LINK-A knockdown/overexpression, chromatin loading assay, cell-cycle FACS analysis, HIF-1α target gene expression Cell reports Medium 37858471
2024 MCM3 subunit coordinates DNA and centrosome duplication, mediating radial glial cell (RGC) attachment to the ventricular zone during cortical neurogenesis; loss of MCMBP (MCM3-7 chaperone) accelerates replication fork speed and disrupts this coordination. Conditional knockout of MCMBP in neural progenitors, DNA fiber assay, immunofluorescence of centrosome and DNA markers, RGC attachment phenotype in mouse bioRxivpreprint Low bio_10.1101_2024.11.05.622174
2026 USP1 deubiquitinase binds MCM3 and stabilizes it via removal of K48-linked ubiquitin chains. Excess MCM3 protein then binds Keap1, disrupting the Keap1-Nrf2 interaction and activating Nrf2 signaling to modulate mitophagy and promote HCC progression. Co-immunoprecipitation of USP1-MCM3, ubiquitin linkage-specific western blotting (K48-linked), Keap1-Nrf2 interaction assay, MCM3 knockdown with mitophagy and Nrf2 readouts, xenograft model iScience Medium 41797940

Source papers

Stage 0 corpus · 82 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Identification of the yeast MCM3-related protein as a component of Xenopus DNA replication licensing factor. Cell 257 7758114
1995 MCM3 complex required for cell cycle regulation of DNA replication in vertebrate cells. Nature 253 7760938
1993 Cell cycle-regulated nuclear localization of MCM2 and MCM3, which are required for the initiation of DNA synthesis at chromosomal replication origins in yeast. Genes & development 210 8224843
1991 Mcm2 and Mcm3, two proteins important for ARS activity, are related in structure and function. Genes & development 184 2044961
1994 DNA polymerase alpha associated protein P1, a murine homolog of yeast MCM3, changes its intranuclear distribution during the DNA synthetic period. The EMBO journal 159 7925275
1992 Properties of the nuclear P1 protein, a mammalian homologue of the yeast Mcm3 replication protein. Nucleic acids research 124 1549468
1990 The phenotype of the minichromosome maintenance mutant mcm3 is characteristic of mutants defective in DNA replication. Molecular and cellular biology 117 2233713
1995 The nuclear envelope prevents reinitiation of replication by regulating the binding of MCM3 to chromatin in Xenopus egg extracts. Current biology : CB 109 8574584
2001 MCM3AP, a novel acetyltransferase that acetylates replication protein MCM3. EMBO reports 76 11258703
2016 Identification and Characterization of MCM3 as a Kelch-like ECH-associated Protein 1 (KEAP1) Substrate. The Journal of biological chemistry 74 27621311
1998 Stability of the replicative Mcm3 protein in proliferating and differentiating human cells. Experimental cell research 73 9633535
1995 Molecular cloning of cDNA encoding mouse Cdc21 and CDC46 homologs and characterization of the products: physical interaction between P1(MCM3) and CDC46 proteins. Nucleic acids research 72 7610039
1997 Mcm2 and Mcm3 are constitutive nuclear proteins that exhibit distinct isoforms and bind chromatin during specific cell cycle stages of Saccharomyces cerevisiae. Molecular biology of the cell 71 9285827
2001 The expression of Ki-67, MCM3, and p27 defines distinct subsets of proliferating, resting, and differentiated cells. The Journal of pathology 64 11745678
2000 A novel nuclear phosphoprotein, GANP, is up-regulated in centrocytes of the germinal center and associated with MCM3, a protein essential for DNA replication. Blood 55 10733502
2008 Phosphorylation of MCM3 on Ser-112 regulates its incorporation into the MCM2-7 complex. Proceedings of the National Academy of Sciences of the United States of America 44 18524952
2019 PLK1 promotes proliferation and suppresses apoptosis of renal cell carcinoma cells by phosphorylating MCM3. Cancer gene therapy 41 31186514
2013 MCM3 as a novel diagnostic marker in benign and malignant salivary gland tumors. Asian Pacific journal of cancer prevention : APJCP 41 23886132
1998 Selective proteolysis of the nuclear replication factor MCM3 in apoptosis. Experimental cell research 40 9473350
2011 Phosphorylation of MCM3 protein by cyclin E/cyclin-dependent kinase 2 (Cdk2) regulates its function in cell cycle. The Journal of biological chemistry 39 21965652
1995 Cdc54 belongs to the Cdc46/Mcm3 family of proteins which are essential for initiation of eukaryotic DNA replication. Gene 38 7698653
2000 Structure, expression, and chromosomal localization of the human gene encoding a germinal center-associated nuclear protein (GANP) that associates with MCM3 involved in the initiation of DNA replication. Gene 37 11024281
2002 The MCM3 acetylase MCM3AP inhibits initiation, but not elongation, of DNA replication via interaction with MCM3. The Journal of biological chemistry 36 12226073
2007 Identification of carboxyl-terminal MCM3 phosphorylation sites using polyreactive phosphospecific antibodies. The Journal of biological chemistry 35 17244605
2023 Pyrroloquinoline quinone alleviates natural aging-related osteoporosis via a novel MCM3-Keap1-Nrf2 axis-mediated stress response and Fbn1 upregulation. Aging cell 31 37365714
2015 Phosphorylation of Minichromosome Maintenance 3 (MCM3) by Checkpoint Kinase 1 (Chk1) Negatively Regulates DNA Replication and Checkpoint Activation. The Journal of biological chemistry 31 25809478
2015 Immunoexpression of Ki-67, MCM2, and MCM3 in Ameloblastoma and Ameloblastic Carcinoma and Their Correlations with Clinical and Histopathological Patterns. Disease markers 31 26823641
1998 Identification of a novel MCM3-associated protein that facilitates MCM3 nuclear localization. The Journal of biological chemistry 30 9712829
2023 m6A demethylase FTO stabilizes LINK-A to exert oncogenic roles via MCM3-mediated cell-cycle progression and HIF-1α activation. Cell reports 27 37858471
2002 MCM3-binding GANP DNA-primase is associated with a novel phosphatase component G5PR. Genes to cells : devoted to molecular & cellular mechanisms 27 12167160
2018 MCM3: A Novel Proliferation Marker in Oral Squamous Cell Carcinoma. Applied immunohistochemistry & molecular morphology : AIMM 26 27258565
2018 Keap1-MCM3 interaction is a potential coordinator of molecular machineries of antioxidant response and genomic DNA replication in metazoa. Scientific reports 26 30108253
1997 Nuclear accumulation of Saccharomyces cerevisiae Mcm3 is dependent on its nuclear localization sequence. Genes to cells : devoted to molecular & cellular mechanisms 25 9427284
2013 Comparison of minichromosome maintenance proteins (MCM-3, MCM-7) and metallothioneins (MT-I/II, MT-III) expression in relation to clinicopathological data in ovarian cancer. Anticancer research 23 24324072
2021 MCM complex members MCM3 and MCM7 are associated with a phenotypic spectrum from Meier-Gorlin syndrome to lipodystrophy and adrenal insufficiency. European journal of human genetics : EJHG 22 33654309
2014 MCM3 could be a better marker than Ki-67 for evaluation of dysplastic oral lesions: an immunohistochemical study. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 22 24456424
2003 Expression of replication-licensing factors MCM2 and MCM3 in normal, hyperplastic, and carcinomatous endometrium: correlation with expression of Ki-67 and estrogen and progesterone receptors. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 22 14501812
2015 Expression of MCM-3 and MCM-7 in Primary Cutaneous T-cell Lymphomas. Anticancer research 21 26504025
2021 MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma. Virchows Archiv : an international journal of pathology 19 34782936
2010 Increase of Mcm3 and Mcm4 expression in cervical squamous cell carcinomas. European journal of gynaecological oncology 19 21077471
2021 MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit. NPJ breast cancer 17 33398005
2003 Genes encoding two essential DNA replication activation proteins, Cdc6 and Mcm3, exhibit very different patterns of expression in the tobacco BY-2 cell cycle. Journal of experimental botany 17 12554713
1999 Involvement of cyclin D1-cdk5 overexpression and MCM3 cleavage in bax-associated spontaneous apoptosis and differentiation in an A253 human head and neck carcinoma xenograft model. International journal of cancer 16 10495426
2018 MCM3 and Ki67 proliferation markers in odontogenic cysts and ameloblastoma. Journal of oral biology and craniofacial research 14 30225187
2015 Evaluation of Minichromosome Maintenance-3 (MCM3) in Oral Squamous Cell Carcinoma. Journal of dentistry (Shiraz, Iran) 14 26046103
2013 The PS1 hairpin of Mcm3 is essential for viability and for DNA unwinding in vitro. PloS one 12 24349215
2002 Two mcm3 mutations affect different steps in the initiation of DNA replication. The Journal of biological chemistry 12 12060653
2002 Mcm3 is polyubiquitinated during mitosis before establishment of the pre-replication complex. The Journal of biological chemistry 12 12200430
1998 cDNA cloning and expression during development of Drosophila melanogaster MCM3, MCM6 and MCM7. Gene 12 9795205
2024 LncRNA GAS6-AS1 contributes to 5-fluorouracil resistance in colorectal cancer by facilitating the binding of PCBP1 with MCM3. Cancer letters 11 38521199
2021 Irisin Association with Ki-67, MCM3 and MT-I/II in Squamous Cell Carcinomas of the Larynx. Biomolecules 11 35053200
2017 Evaluation of the Ki-67 and MCM3 Expression in Cytologic Smear of Oral Squamous Cell Carcinoma. Journal of dentistry (Shiraz, Iran) 11 29034276
2016 Up-regulation of MCM3 Relates to Neuronal Apoptosis After Traumatic Brain Injury in Adult Rats. Cellular and molecular neurobiology 9 27401074
2014 Evolutionary diversification of MCM3 genes in Xenopus laevis and Danio rerio. Cell cycle (Georgetown, Tex.) 9 25485507
2017 Expression of p53 and selected proliferative markers (Ki-67, MCM3, PCNA, and topoisomerase IIα) in borderline ovarian tumors: Correlation with clinicopathological features. Histology and histopathology 8 28493257
2013 In vitro study on the effect of doxorubicin on the proliferation markers MCM3 and Ki-67. Journal of B.U.ON. : official journal of the Balkan Union of Oncology 8 24344040
2021 MCM3 proliferative index is worthier over Ki-67 in the characterization of salivary gland tumors. Indian journal of pathology & microbiology 5 33433405
2018 CDK phosphorylation regulates Mcm3 degradation in budding yeast. Biochemical and biophysical research communications 5 30376991
2016 Mcm3 replicative helicase mutation impairs neuroblast proliferation and memory in Drosophila. Genes, brain, and behavior 5 27283469
2000 Genomic structure of the gene for the human P1 protein (MCM3) and its exclusion as a candidate for autosomal recessive polycystic kidney disease. European journal of human genetics : EJHG 5 10780780
2023 Rac GTPase activating protein 1 promotes the glioma growth by regulating the expression of MCM3. Translational oncology 4 37595394
2022 Systematic analysis of MCM3 in pediatric medulloblastoma via multi-omics analysis. Frontiers in molecular biosciences 4 36133906
2021 The Immunohistochemical Expression of MCM-3, -5, and -7 Proteins in the Uterine Fibroids. Current issues in molecular biology 4 34449552
2018 MCM interference during licensing of DNA replication in Xenopus egg extracts-Possible Role of a C-terminal region of MCM3. Cell cycle (Georgetown, Tex.) 4 29261034
2025 Gobal crotonylome reveals that HNRNPC and its crotonylation promote p53-deficient tumor growth by stabilizing CCND1 and MCM3 mRNAs. Cancer letters 3 40482911
2024 A novel upregulated hsa_circ_0032746 regulates the oncogenesis of esophageal squamous cell carcinoma by regulating miR-4270/MCM3 axis. Human genomics 3 38200573
2024 Expression, potential biological behaviour and clinical significance of MCM3 in pancreatic adenocarcinoma: a comprehensive study integrating high throughput sequencing, CRISPR screening and in-house immunohistochemistry. Annals of medicine 3 39310930
2023 Quantitative Proteomic Analysis of MCM3 in ThinPrep Samples of Patients with Cervical Preinvasive Cancer. International journal of molecular sciences 3 37445651
2022 Corrigendum: Systematic analysis of MCM3 in pediatric medulloblastoma via multi-omics analysis. Frontiers in molecular biosciences 3 36452454
2016 Comparison between immunohistochemical expression of Ki-67 and MCM-3 in major salivary gland epithelial tumors in children and adolescents. Preliminary study. Polish journal of pathology : official journal of the Polish Society of Pathologists 3 28547962
2025 MCM3 promotes hepatocellular carcinoma progression via Epithelial-mesenchymal Transition through AKT/Twist signaling pathway. Annals of hepatology 2 39978465
2023 Expression analysis of cyclin D, Ki-67, MCM3 and MCM2 in oral squamous cell carcinoma. Bioinformation 2 38415027
2018 Regulation of the Minichromosome Maintenance Protein 3 (MCM3) Chromatin Binding by the Prolyl Isomerase Pin1. Journal of molecular biology 2 30316783
2017 [Deguelin inhibits proliferation and regulates the expression of MCM3-CDC45 in MCF-7 and H1299 cells in vitro]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 2 29180339
2010 Human cytomegalovirus IE86 protein binds to cellular Mcm3 protein but does not inhibit its binding to the Epstein-Barr virus oriP in U373MG-p220.2 cells. Acta virologica 2 20545442
2023 Immunohistochemical Comparison of Ki-67 and MCM-3 in Odontogenic Cysts: An Observational Study. Applied immunohistochemistry & molecular morphology : AIMM 1 38062794
2021 Downregulation of circular RNA circDOCK7 identified from diabetic rats after sleeve gastrectomy contributes to hepatocyte apoptosis through regulating miR-139-3p and MCM3. Biochemical and biophysical research communications 1 33640606
2026 A cancer-specific pipeline uncovers MCM3 as a driver of glioblastoma progression via suppression of the Wnt pathway. International journal of biological macromolecules 0 41638282
2026 USP1 promotes hepatocellular carcinoma progression by modulating mitophagy via stabilizing MCM3 to regulate the Keap1-Nrf2 axis. iScience 0 41797940
2025 Sequence specificity of an essential nuclear localization sequence in Mcm3. PLoS genetics 0 39836669
2025 ZMIZ2/MCM3 Axis Participates in Triple-Negative Breast Cancer Progression. Oncology research 0 41502508
2024 Sequence specificity of an essential nuclear localization sequence in Mcm3. bioRxiv : the preprint server for biology 0 39605614

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