MCM2

Summary

MCM2 (minichromosome maintenance complex component 2, HGNC:6944) is a protein-coding gene on chromosome 3q21.3, encoding DNA replication licensing factor MCM2 (P49736). 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.

The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are involved in the initiation of eukaryotic genome replication. The hexameric protein complex formed by MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein forms a complex with MCM4, 6, and 7, and has been shown to regulate the helicase activity of the complex. This protein is phosphorylated, and thus regulated by, protein kinases CDC2 and CDC7. Multiple alternatively spliced transcript variants have been found, but the full-length nature of some variants has not been defined.

Source: NCBI Gene 4171 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant nonsyndromic hearing loss 70 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 401 total — 2 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_004526

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6944
Approved symbol	MCM2
Name	minichromosome maintenance complex component 2
Location	3q21.3
Locus type	gene with protein product
Status	Approved
Aliases	D3S3194, KIAA0030, BM28, cdc19, DFNA70
Ensembl gene	ENSG00000073111
Ensembl biotype	protein_coding
OMIM	116945
Entrez	4171

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000265056, ENST00000468414, ENST00000468659, ENST00000472731, ENST00000473785, ENST00000474964, ENST00000477668, ENST00000480910, ENST00000491422, ENST00000927678, ENST00000927679, ENST00000927680

RefSeq mRNA: 1 — MANE Select: NM_004526 NM_004526

CCDS: CCDS3043

Canonical transcript exons

ENST00000265056 — 16 exons

Exon	Start	End
ENSE00001128282	127621663	127622436
ENSE00001913826	127598411	127598472
ENSE00003470282	127616868	127617118
ENSE00003473038	127617969	127618081
ENSE00003493668	127621073	127621228
ENSE00003507521	127615862	127615955
ENSE00003575708	127608382	127608516
ENSE00003601057	127599318	127599547
ENSE00003603827	127617279	127617405
ENSE00003637362	127604896	127605156
ENSE00003643982	127620698	127620880
ENSE00003644796	127606118	127606337
ENSE00003651853	127608832	127609023
ENSE00003657441	127606610	127606817
ENSE00003683720	127619027	127619278
ENSE00003789885	127604608	127604783

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 98.99.

FANTOM5 (CAGE): breadth broad, TPM avg 0.6127 / max 16.8092, expressed in 311 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45287	110.2871	1825
38384	43.3283	1733
38385	0.6127	311

Top tissues by expression

278 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	98.99	gold quality
secondary oocyte	CL:0000655	98.67	gold quality
ventricular zone	UBERON:0003053	98.36	gold quality
embryo	UBERON:0000922	96.76	gold quality
ganglionic eminence	UBERON:0004023	96.46	gold quality
endometrium epithelium	UBERON:0004811	95.58	gold quality
trabecular bone tissue	UBERON:0002483	91.40	gold quality
bone marrow cell	CL:0002092	90.69	gold quality
bone marrow	UBERON:0002371	90.67	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.10	gold quality
tongue squamous epithelium	UBERON:0006919	88.39	silver quality
gingival epithelium	UBERON:0001949	88.23	gold quality
vermiform appendix	UBERON:0001154	86.27	gold quality
stromal cell of endometrium	CL:0002255	86.03	gold quality
hair follicle	UBERON:0002073	86.00	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.97	gold quality
esophagus squamous epithelium	UBERON:0006920	85.94	gold quality
squamous epithelium	UBERON:0006914	85.78	gold quality
epithelium of nasopharynx	UBERON:0001951	85.66	gold quality
nasopharynx	UBERON:0001728	85.65	gold quality
gingiva	UBERON:0001828	85.60	gold quality
placenta	UBERON:0001987	85.51	gold quality
tibia	UBERON:0000979	85.32	gold quality
thymus	UBERON:0002370	85.28	gold quality
mucosa of transverse colon	UBERON:0004991	85.22	gold quality
ileal mucosa	UBERON:0000331	85.10	gold quality
epithelium of esophagus	UBERON:0001976	85.08	gold quality
sural nerve	UBERON:0015488	84.11	gold quality
caecum	UBERON:0001153	83.52	gold quality
lymph node	UBERON:0000029	83.21	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	508.40
E-GEOD-100618	yes	291.91
E-ENAD-20	yes	239.31
E-MTAB-7037	yes	172.18
E-ANND-3	yes	6.87
E-MTAB-6379	no	237.40

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
SNF8	Unknown

Upstream regulators (CollecTRI, top): E2F2, MYCN, NOTCH1, RBPJ

miRNA regulators (miRDB)

19 targeting MCM2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-4272	98.76	68.74	1810
HSA-MIR-500A-5P	98.76	69.13	1241
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-6764-3P	98.44	67.64	1153
HSA-MIR-6824-3P	98.44	67.62	1154
HSA-MIR-3151-3P	97.80	66.16	479
HSA-MIR-1224-3P	97.24	65.92	851

Literature-anchored findings (GeneRIF, showing 40)

• MCM2 is a sensitive marker for premalignant lung cells since it is present in cells at the surface of metaplastic lung lesions, which are more likely to be exfoliated into sputum. (PMID:11472637)
• Functional analysis of the mouse homolog (PMID:11568184)
• Functional analysis of the Xenopus homolog (PMID:11864598)
• MCM2(Minichromosome Maintenance 2) is regulated via a P53-independent pathway, and a useful biomarker of proliferating cells. (PMID:11872961)
• Functional analysis of the Xenopus homolog (PMID:12087101)
• MCM2 expression in fibrous histiocytoma correlates with cell proliferation.Its expression is ubiquitous in proliferating cells, regardless of the expression of P53. MCM2 might be a reliable marker of proliferating cells in human MFH. (PMID:12119552)
• role of AKAP95 in DNA replication by providing a scaffold for MCM2 (PMID:12740381)
• Increased expression of minichromosome maintenance protein-2 and Ki67 is associated with laryngeal squamous epithelial lesions (PMID:12966424)
• ATM/ATR-dependent (ataxia-telangiectasia-mutated/ATM- and Rad3-related) checkpoint pathways are directly linked to three members of the MCM complex(MCM2,MCM3,MCM7). (PMID:15210935)
• pairwise interactions of individual human MCM subunits by using the yeast two-hybrid system and in vivo protein-protein crosslinking (PMID:15236977)
• purified hRad51 and hRad52 interact with each other as well as with Mini chromosome maintenance (MCM) proteins in HeLa cell extracts (PMID:15766559)
• the majority of the Mcm2 isoforms phosphorylated by Cdc7 are not stably associated with chromatin (PMID:16446360)
• The MCM2 protein expression was associated with the highest levels of proliferation, suggesting a synergistic effect. (PMID:16609045)
• The combination of MCM2, geminin and Ki67 could represent a valuable tool in the understanding of hepatocellular carcinoma progression in cirrhosis. (PMID:16629645)
• MCM2 is a helpful marker for differentiating follicular carcinoma and follicular adenoma of the thyroid. (PMID:16722928)
• Results describe the mapping of the sites in human Mcm2 protein that are phosphorylated by Cdc7. (PMID:16864800)
• higher expression in MCM2 and gelsolin was significantly associated with poorer prognosis in patients with NSCLC, which suggests that higher tumor proliferation and motility may be important in the prognosis of NSCLC (PMID:16882345)
• Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. (PMID:16899510)
• Immunoreactivity for p16, MCM2, and TOP IIA was detected in only 76% of cases in low-grade squamous intraepitelial lesions (LSIL). (PMID:17512033)
• MCM2 is part of the GINS complex. (PMID:17557111)
• MCM-2 and MCM-5 proteins appear to be promising as prognostic markers in patients with ovarian adenocarcinomas. (PMID:17940502)
• exogenous Cdt1 induces re-replication by de-repressing endogenous Cdt1 through the titration of PCNA and cyclin; Cdt1 lacking the evolutionarily conserved region that interacts with MCM2-7 is capable of inducing re-replication (PMID:18184650)
• Results strongly suggest that the MCM2 fragments derived from the C-terminal region inhibit DNA helicase activity through their ability to bind to ssDNA. (PMID:18190532)
• may be a sensitive proliferation marker in salivary gland tumours (PMID:18248354)
• MCM protein 2 is present in melanocytes from benign nevi, dysplastic nevi, primary cutaneous melanomas, and cutaneous melanoma metastases. (PMID:18249467)
• Cdc7/Dbf4 kinase activity inhibition affects specific phosphorylation sites on MCM2 in cancer cells (PMID:18286467)
• In colon cancer, MCM2 expression was associated with the tumors’ histological grade, existence of nodular metastases, malignancy on adenoma, and vascular invasion. (PMID:18465232)
• Minichromosome maintenance protein 2 is a useful proliferative marker of breast carcinoma. (PMID:18774496)
• MCM2 expression was observed in the basal third to half of the colonic crypts in normal mucosa, but throughout colonic adenocarcinoma and adenoma epithelia. However, expression of MCM2 in adenocarcinomas was significantly higher than in adenomas. (PMID:18803052)
• MCM-2 fragment is upregulated in senescence, quiescence, and differentiation (PMID:19001846)
• absence of multiple MCM2 transcripts implied a possible posttranslational molecular cleavage in generation of the MCM2-related fragment, and a potential functional role in the regulation of the activity of the MCM protein complex. (PMID:19001876)
• The potential value of MCM2 in early diagnosis of colorectal cancer. (PMID:19077563)
• MCM7 is a more reliable marker than MCM2 or Ki-67 in lung adenocarcinomas (PMID:19144445)
• Lymphocyte Mcm-2 expression is a useful adjunct to histology in differentiating between hepatitis C virus graft infection and acute cellular rejection. (PMID:19243005)
• the MCM2-7 proteins are co-localized with RNA Pol II on chromatins of constitutively transcribing genes, and MCM5 is required for transcription elongation of RNA Pol II. (PMID:19318354)
• MCM2 does not appear useful in differentiating basal cell carcinomas with follicular differentiation from trichoepitheliomas (PMID:19522849)
• Phosphorylation of Mcm2 by Cdc7 kinase promotes chromatin loading of Mcm2. (PMID:19647517)
• Replisome factors MCM10, MCM2and MCM7 helicase, are the primary interaction partner proteins of human RECQ4. (PMID:19696745)
• interactions between Cdc45, Mcm2-7, and the GINS complex (collectively called the CMG complex), which seem to play a key role in the formation and progression of replication forks (PMID:19805216)
• Mcm2 index showed a significant association with pituitary tumor extension (p = 0.02), but not with tumor invasion. (PMID:20174894)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mcm2	ENSDARG00000102798
mus_musculus	Mcm2	ENSMUSG00000002870
rattus_norvegicus	Mcm2	ENSRNOG00000016316
drosophila_melanogaster	Mcm2	FBGN0014861
caenorhabditis_elegans		WBGENE00003154

Paralogs (8): MCM6 (ENSG00000076003), MCM5 (ENSG00000100297), MCM4 (ENSG00000104738), MCM9 (ENSG00000111877), MCM3 (ENSG00000112118), MCM8 (ENSG00000125885), MCM7 (ENSG00000166508), MCMDC2 (ENSG00000178460)

Protein

Protein identifiers

DNA replication licensing factor MCM2 — P49736 (reviewed: P49736)

Alternative names: Minichromosome maintenance protein 2 homolog, Nuclear protein BM28

All UniProt accessions (6): P49736, C9J013, C9JZ21, F8WDM3, H0Y8E6, H7C4N9

UniProt curated annotations — full annotation on UniProt →

Function. 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. 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. Required for the entry in S phase and for cell division. Plays a role in terminally differentiated hair cells development of the cochlea and induces cells apoptosis.

Subunit / interactions. Component of the MCM2-7 complex. The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5. Component of the CMG helicase complex, a hexameric ring of related MCM2-7 subunits stabilized by CDC45 and the tetrameric GINS complex. Interacts with DBF4. Interacts with KAT7. May interact with MCM10. Component of the replisome complex composed of at least DONSON, MCM2, MCM7, PCNA and TICRR. Forms a co-chaperone complex with DNAJC9 and histone H3.3-H4 heterodimers. Within the complex, interacts (via N-terminus) with DNAJC9 (via C-terminus); the interaction is histone-dependent. Interacts with histones H3.1 and H3.3. Interacts with AGER/RAGE; the interaction is increased following DNA replication stress and stabilizes the MCM2-7 complex at replication forks.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. Phosphorylated on Ser-108 by ATR in proliferating cells. Ser-108 proliferation is increased by genotoxic agents. Ser-40 is mediated by the CDC7-DBF4 and CDC7-DBF4B complexes, while Ser-53 phosphorylation is only mediated by the CDC7-DBF4 complex. Phosphorylation by the CDC7-DBF4 complex during G1/S phase is required for the initiation of DNA replication.

Disease relevance. Deafness, autosomal dominant, 70 (DFNA70) [MIM:616968] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA70 is characterized by slowly progressive, postlingual hearing impairment. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. Specifically a MCM467 subcomplex is shown to have in vitro helicase activity which is inhibited by the MCM2 subunit. The MCM2-7 hexamer is the proposed physiological active complex.

Similarity. Belongs to the MCM family.

RefSeq proteins (1): NP_004517* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001208	MCM_dom	Domain
IPR008045	MCM2	Family
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR018525	MCM_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR027925	MCM_N	Domain
IPR031327	MCM	Family
IPR033762	MCM_OB	Domain
IPR041562	MCM_lid	Domain
IPR059098	WHD_MCM2	Domain

Pfam: PF00493, PF12619, PF14551, PF17207, PF17855, PF23669

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (124 total): helix 31, strand 28, modified residue 18, turn 10, sequence variant 8, sequence conflict 6, region of interest 5, mutagenesis site 5, compositionally biased region 3, short sequence motif 2, binding site 2, initiator methionine 1, chain 1, site 1, domain 1, zinc finger region 1, cross-link 1

Structure

Experimental structures (PDB)

39 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6YA7	X-RAY DIFFRACTION	1.67
7CIZ	X-RAY DIFFRACTION	1.8
5BNX	X-RAY DIFFRACTION	2.31
5JA4	X-RAY DIFFRACTION	2.42
7CJ0	X-RAY DIFFRACTION	2.5
7W1Y	ELECTRON MICROSCOPY	2.59
9E2Z	ELECTRON MICROSCOPY	2.6
5BNV	X-RAY DIFFRACTION	2.79
7PLO	ELECTRON MICROSCOPY	2.8
8W0F	ELECTRON MICROSCOPY	2.8
4UUZ	X-RAY DIFFRACTION	2.9
5BO0	X-RAY DIFFRACTION	2.91
8S09	ELECTRON MICROSCOPY	3.1
7PFO	ELECTRON MICROSCOPY	3.2
8S0A	ELECTRON MICROSCOPY	3.2
9CAQ	ELECTRON MICROSCOPY	3.2
9LXD	ELECTRON MICROSCOPY	3.27
6XTX	ELECTRON MICROSCOPY	3.29
22VT	ELECTRON MICROSCOPY	3.3
8B9D	ELECTRON MICROSCOPY	3.4
8W0E	ELECTRON MICROSCOPY	3.4
9VLN	ELECTRON MICROSCOPY	3.42
9UQ0	ELECTRON MICROSCOPY	3.47
5C3I	X-RAY DIFFRACTION	3.5
8W0I	ELECTRON MICROSCOPY	3.5
8S0B	ELECTRON MICROSCOPY	3.6
8S0D	ELECTRON MICROSCOPY	3.6
8S0E	ELECTRON MICROSCOPY	3.8
8W0G	ELECTRON MICROSCOPY	3.8
9LXF	ELECTRON MICROSCOPY	3.86

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49736-F1	76.54	0.17

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 656 (arginine finger)

Ligand- & substrate-binding residues (2): 530; 531

Post-translational modifications (19): 2, 12, 13, 25, 26, 27, 32, 39, 40, 41, 53, 59, 108, 137, 139, 216, 381, 484, 178

Mutagenesis-validated functional residues (5):

Position	Phenotype
27	impairs atpase activity of the mcm-2-7 complex and reduces phosphorylation by the cdc7-dbf4 complex; when associated wit
41	impairs atpase activity of the mcm-2-7 complex and reduces phosphorylation by the cdc7-dbf4 complex; when associated wit
81–90	loss of interaction with dnajc9.
108	reduces phosphorylation by atr.
139	impairs atpase activity of the mcm-2-7 complex and reduces phosphorylation by the cdc7-dbf4 complex; when associated wit

Function

Pathways and Gene Ontology

Reactome pathways

21 pathways

ID	Pathway
R-HSA-176187	Activation of ATR in response to replication stress
R-HSA-176974	Unwinding of DNA
R-HSA-68867	Assembly of the pre-replicative complex
R-HSA-68949	Orc1 removal from chromatin
R-HSA-68962	Activation of the pre-replicative complex
R-HSA-69052	Switching of origins to a post-replicative state
R-HSA-9825895	Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence
R-HSA-1266738	Developmental Biology
R-HSA-1640170	Cell Cycle
R-HSA-453279	Mitotic G1 phase and G1/S transition
R-HSA-69002	DNA Replication Pre-Initiation
R-HSA-69190	DNA strand elongation
R-HSA-69206	G1/S Transition
R-HSA-69239	Synthesis of DNA
R-HSA-69242	S Phase
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-69306	DNA Replication
R-HSA-69481	G2/M Checkpoints
R-HSA-69620	Cell Cycle Checkpoints
R-HSA-9730414	MITF-M-regulated melanocyte development
R-HSA-9856651	MITF-M-dependent gene expression

MSigDB gene sets: 789 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, E2F_Q4, KALMA_E2F1_TARGETS, MORF_DNMT1, WU_APOPTOSIS_BY_CDKN1A_VIA_TP53, REACTOME_DNA_REPLICATION, MODULE_52, E2F_Q4_01, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, MORF_ESPL1, GNF2_CENPF, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, E2F4DP1_01, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION

GO Biological Process (9): double-strand break repair via break-induced replication (GO:0000727), DNA replication (GO:0006260), DNA replication initiation (GO:0006270), nucleosome assembly (GO:0006334), apoptotic process (GO:0006915), regulation of DNA-templated DNA replication initiation (GO:0030174), cellular response to interleukin-4 (GO:0071353), cochlea development (GO:0090102), mitotic DNA replication initiation (GO:1902975)

GO Molecular Function (16): DNA binding (GO:0003677), DNA helicase activity (GO:0003678), DNA replication origin binding (GO:0003688), single-stranded DNA binding (GO:0003697), ATP binding (GO:0005524), zinc ion binding (GO:0008270), ATP hydrolysis activity (GO:0016887), enzyme binding (GO:0019899), histone binding (GO:0042393), nucleotide binding (GO:0000166), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787), single-stranded DNA helicase activity (GO:0017116), 3’-5’ DNA helicase activity (GO:0043138), metal ion binding (GO:0046872)

GO Cellular Component (12): chromosome, telomeric region (GO:0000781), chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear origin of replication recognition complex (GO:0005664), cytoplasm (GO:0005737), cytosol (GO:0005829), cilium (GO:0005929), MCM complex (GO:0042555), CMG complex (GO:0071162), nuclear chromosome (GO:0000228), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
DNA Replication Pre-Initiation	2
Synthesis of DNA	2
Cell Cycle, Mitotic	2
DNA Replication	2
Cell Cycle	2
G2/M Checkpoints	1
DNA strand elongation	1
Switching of origins to a post-replicative state	1
G1/S Transition	1
MITF-M-dependent gene expression	1
Mitotic G1 phase and G1/S transition	1
S Phase	1
Cell Cycle Checkpoints	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
DNA metabolic process	2
ATP-dependent activity	2
protein binding	2
DNA helicase activity	2
chromosome	2
nuclear lumen	2
nuclear chromosome	2
double-strand break repair via homologous recombination	1
DNA biosynthetic process	1
DNA-templated DNA replication	1
chromatin organization	1
nucleosome organization	1
protein-DNA complex assembly	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
DNA replication initiation	1
regulation of DNA-templated DNA replication	1
response to interleukin-4	1
cellular response to cytokine stimulus	1
inner ear development	1
anatomical structure development	1
nuclear cell cycle DNA replication initiation	1
mitotic DNA replication	1
mitotic cell cycle process	1
nucleic acid binding	1
helicase activity	1
ATP-dependent activity, acting on DNA	1
sequence-specific double-stranded DNA binding	1
DNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
ribonucleoside triphosphate phosphatase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
binding	1

Protein interactions and networks

STRING

2792 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCM2	CDC6	Q99741	844
MCM2	CDT1	Q9H211	819
MCM2	MCM4	P33991	714
MCM2	GINS1	Q14691	702
MCM2	CDC45	O75419	701
MCM2	GINS4	Q9BRT9	692
MCM2	GINS3	Q9BRX5	645
MCM2	MCM7	P33993	634
MCM2	ASF1B	Q9NVP2	620
MCM2	CDK1	P06493	614
MCM2	MCM5	P33992	607
MCM2	EGFR	P00533	588
MCM2	MCM6	Q14566	582
MCM2	ORC4	O43929	563
MCM2	DBF4	Q9UBU7	557

IntAct

277 interactions, top by confidence:

A	B	Type	Score
MCM2	MCM6	psi-mi:“MI:0915”(physical association)	0.950
MCM6	MCM2	psi-mi:“MI:0915”(physical association)	0.950
PRKAG1	PRKAB2	psi-mi:“MI:0914”(association)	0.940
MCM2	MCM7	psi-mi:“MI:0407”(direct interaction)	0.940
MCM7	MCM4	psi-mi:“MI:0914”(association)	0.930
MCM2	MCM3	psi-mi:“MI:0915”(physical association)	0.920
MCM2	MCM3	psi-mi:“MI:0407”(direct interaction)	0.920
MCM2	MCM3	psi-mi:“MI:0914”(association)	0.920
ASF1A	MCM2	psi-mi:“MI:0915”(physical association)	0.890
ASF1A	MCM2	psi-mi:“MI:0914”(association)	0.890
MCM2	ASF1A	psi-mi:“MI:0915”(physical association)	0.890
MCM2	MCM4	psi-mi:“MI:0914”(association)	0.830
MCM6	MCM3	psi-mi:“MI:0914”(association)	0.810
MCM2	MCM5	psi-mi:“MI:0407”(direct interaction)	0.800
PLK1	SPAG9	psi-mi:“MI:0914”(association)	0.790
MCM2	ASF1B	psi-mi:“MI:0914”(association)	0.770
ASF1B	MCM2	psi-mi:“MI:0915”(physical association)	0.770
CDK19	MED19	psi-mi:“MI:0914”(association)	0.770
MCM2	H4C16	psi-mi:“MI:0914”(association)	0.750

BioGRID (1403): MCM2 (Affinity Capture-MS), MCM2 (Affinity Capture-MS), MCM6 (Two-hybrid), MCM2 (Affinity Capture-MS), MCM2 (Affinity Capture-MS), MCM2 (Affinity Capture-MS), MCM2 (Affinity Capture-MS), MCM2 (Affinity Capture-MS), MCM2 (Affinity Capture-MS), MCM2 (Affinity Capture-MS), MCM2 (Affinity Capture-MS), MCM2 (Affinity Capture-MS), MCM2 (Affinity Capture-MS), MCM2 (Affinity Capture-MS), MCM2 (Affinity Capture-MS)

ESM2 similar proteins: A4FUD9, B8AZ99, B8AZX3, F4KAB8, O75001, O80786, P25205, P25206, P29458, P30666, P33992, P34647, P41389, P49718, P49731, P49735, P49736, P49739, P55861, P97310, P97311, Q0DHC4, Q14566, Q28BS0, Q28CM3, Q29JI9, Q2KIZ8, Q43704, Q498J7, Q5FWY4, Q5R8G6, Q5ZMN2, Q61J08, Q62724, Q6DIH3, Q6F353, Q6P1V8, Q6PCI7, Q7Q0Q1, Q7ZXB1

Diamond homologs: A4FUD9, B8AEH3, B8AZ14, B8AZ99, B8AZX3, B8B406, B8BKI8, B8BMI1, B9FKM7, D3ZVK1, E1BPX4, F1M5F3, F1N2W9, F1QDI9, F4KAB8, I0IUP3, I0IUP4, O75001, O80786, P24279, P25205, P25206, P29458, P29469, P29496, P30664, P30665, P30666, P33991, P33992, P33993, P34647, P38132, P40377, P41389, P43299, P49717, P49718, P49731, P49735

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
ATR	unknown	MCM2	phosphorylation
CDC7	up-regulates	MCM2	phosphorylation
CDK2	up-regulates	MCM2	phosphorylation
CSNK2A1	up-regulates	MCM2	phosphorylation
MCM2	“form complex”	MCM	binding
CDK7	“up-regulates activity”	MCM2	phosphorylation
CDT1	“up-regulates activity”	MCM2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 152 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of the pre-replicative complex	11	30.4×	8e-12
Activation of ATR in response to replication stress	11	28.0×	1e-11
DNA Replication Pre-Initiation	8	21.5×	3e-08
Synthesis of DNA	8	20.4×	4e-08
G1/S Transition	10	19.8×	2e-09
Assembly of the ORC complex at the origin of replication	14	19.6×	4e-12
Mitotic G1 phase and G1/S transition	12	18.7×	1e-10
Packaging Of Telomere Ends	10	18.6×	3e-09

GO biological processes:

GO term	Partners	Fold	FDR
DNA replication initiation	10	44.0×	5e-12
regulation of DNA-templated DNA replication initiation	5	37.1×	3e-05
nucleosome assembly	17	16.8×	2e-13
heterochromatin formation	9	16.2×	9e-07
DNA replication	12	14.0×	2e-08
positive regulation of fibroblast proliferation	5	10.4×	1e-02
double-strand break repair	6	8.6×	8e-03
regulation of cell cycle	12	6.3×	7e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

401 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	218
Likely benign	117
Benign	26

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
489243	NM_004526.4(MCM2):c.1901-1G>C	Likely pathogenic
988335	NM_004526.4(MCM2):c.920G>C (p.Arg307Pro)	Likely pathogenic

SpliceAI

1980 predictions. Top by Δscore:

Variant	Effect	Δscore
3:127599313:TGCAG:T	acceptor_loss	1.0000
3:127599315:CA:C	acceptor_loss	1.0000
3:127599316:A:AG	acceptor_gain	1.0000
3:127599316:A:AT	acceptor_loss	1.0000
3:127599316:AG:A	acceptor_gain	1.0000
3:127599317:G:GG	acceptor_gain	1.0000
3:127599317:GG:G	acceptor_gain	1.0000
3:127599317:GGA:G	acceptor_gain	1.0000
3:127599317:GGAA:G	acceptor_gain	1.0000
3:127599317:GGAAT:G	acceptor_gain	1.0000
3:127599462:GA:G	donor_gain	1.0000
3:127599544:A:T	donor_gain	1.0000
3:127599545:AAGGT:A	donor_loss	1.0000
3:127599546:AGG:A	donor_loss	1.0000
3:127599548:G:C	donor_loss	1.0000
3:127599549:T:A	donor_loss	1.0000
3:127604604:TCAGG:T	acceptor_loss	1.0000
3:127604606:A:AG	acceptor_gain	1.0000
3:127604606:A:C	acceptor_loss	1.0000
3:127604606:AG:A	acceptor_gain	1.0000
3:127604606:AGG:A	acceptor_gain	1.0000
3:127604607:G:GG	acceptor_gain	1.0000
3:127604607:GG:G	acceptor_gain	1.0000
3:127604607:GGG:G	acceptor_gain	1.0000
3:127604607:GGGA:G	acceptor_gain	1.0000
3:127604607:GGGAC:G	acceptor_gain	1.0000
3:127604779:GTATG:G	donor_gain	1.0000
3:127604783:GGTA:G	donor_loss	1.0000
3:127604784:G:C	donor_loss	1.0000
3:127604784:G:GG	donor_gain	1.0000

AlphaMissense

6008 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:127606770:T:C	C352R	1.000
3:127615909:G:C	K492N	1.000
3:127615909:G:T	K492N	1.000
3:127616904:T:C	L520P	1.000
3:127616912:G:A	G523R	1.000
3:127616912:G:C	G523R	1.000
3:127616913:G:A	G523E	1.000
3:127616913:G:T	G523V	1.000
3:127616921:G:C	G526R	1.000
3:127616922:G:A	G526D	1.000
3:127616928:C:A	A528E	1.000
3:127616930:A:C	K529Q	1.000
3:127616932:G:C	K529N	1.000
3:127616932:G:T	K529N	1.000
3:127616933:T:C	S530P	1.000
3:127616943:T:C	L533P	1.000
3:127616988:G:A	G548D	1.000
3:127617008:G:C	G555R	1.000
3:127617009:G:A	G555D	1.000
3:127617012:T:A	L556H	1.000
3:127617012:T:C	L556P	1.000
3:127617018:C:A	A558E	1.000
3:127617024:T:A	V560D	1.000
3:127617065:G:T	G574W	1.000
3:127617097:T:G	C584W	1.000
3:127617104:G:C	D587H	1.000
3:127617105:A:C	D587A	1.000
3:127617105:A:T	D587V	1.000
3:127617106:T:A	D587E	1.000
3:127617106:T:G	D587E	1.000

dbSNP variants (sampled 300 via entrez): RS1000044439 (3:127614995 A>G), RS1000111676 (3:127609669 T>A), RS1000143031 (3:127609318 C>A,T), RS1000201515 (3:127621520 C>A,T), RS1000312223 (3:127615291 A>G), RS1000444638 (3:127616491 C>T), RS1000492836 (3:127598352 A>C,G), RS1000609215 (3:127598172 G>T), RS1000674269 (3:127604675 G>A), RS1000710714 (3:127598816 A>C,G), RS1000997594 (3:127616811 C>T), RS1001107797 (3:127604358 A>G), RS1001113798 (3:127610994 G>A), RS1001148080 (3:127610635 G>T), RS1001203922 (3:127622747 G>A,T)

Disease associations

OMIM: gene MIM:116945 | disease phenotypes: MIM:616968

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant nonsyndromic hearing loss 70	Strong	Autosomal dominant
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant
nonsyndromic genetic hearing loss	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Limited	AD

Mondo (3): autosomal dominant nonsyndromic hearing loss 70 (MONDO:0014853), nonsyndromic genetic hearing loss (MONDO:0019497), autosomal dominant nonsyndromic hearing loss (MONDO:0019587)

Orphanet (1): Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004250_16	Alanine aminotransferase (ALT) levels after remission induction therapy in actute lymphoblastic leukemia (ALL)	2.000000e-06
GCST006190_62	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-08
GCST010002_438	Refractive error	9.000000e-21
GCST90002404_51	Red cell distribution width	7.000000e-12

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007965	response to combination chemotherapy
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0009188	Red cell distribution width

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3308910 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.62	Kd	2.398	nM	CHEMBL5653589
8.62	ED50	2.398	nM	CHEMBL5653589
5.47	Kd	3386	nM	CHEMBL3752910
5.47	ED50	3386	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 25 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148730: Binding affinity to human MCM2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0024	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148730: Binding affinity to human MCM2 incubated for 45 mins by Kinobead based pull down assay	kd	3.3861	uM

CTD chemical–gene interactions

138 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects binding, decreases reaction, affects cotreatment, decreases expression	8
bisphenol A	affects expression, affects cotreatment, increases methylation, decreases expression, increases expression	7
Benzo(a)pyrene	increases expression, affects methylation, decreases expression	5
Estradiol	decreases reaction, increases expression, affects phosphorylation	5
Arsenic Trioxide	affects binding, decreases reaction, increases expression	4
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, affects expression	4
Air Pollutants	increases abundance, increases oxidation, decreases expression, increases expression, affects cotreatment	3
Cannabidiol	decreases expression	3
Cisplatin	decreases expression, increases expression	3
Cyclosporine	affects expression, decreases expression	3
Zoledronic Acid	affects cotreatment, decreases expression	2
Copper	affects binding, decreases expression	2
Niclosamide	decreases expression	2
Parathion	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Quercetin	decreases expression, increases phosphorylation	2
Smoke	decreases expression, increases abundance, increases expression	2
Tretinoin	affects cotreatment, decreases expression	2
Aflatoxin B1	affects expression, increases expression	2
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
TAK-243	decreases sumoylation	1
lasiocarpine	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
propionaldehyde	decreases expression	1
geraniol	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects response to substance, affects expression	1
methylselenic acid	affects expression	1

ChEMBL screening assays

22 unique, capped per target: 22 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1225135	Binding	Inhibition of Mcm2 phosphorylation in human A2780 cells after 24 hrs	A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity. — Nat Chem Biol

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations