MCM3

Summary

MCM3 (minichromosome maintenance complex component 3, HGNC:6945) is a protein-coding gene on chromosome 6p12.2, encoding DNA replication licensing factor MCM3 (P25205). 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. It is a selective cancer dependency (DepMap: 85.2% of cell lines).

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 is a subunit of the protein complex that consists of MCM2-7. It has been shown to interact directly with MCM5/CDC46. This protein also interacts with and is acetylated by MCM3AP, a chromatin-associated acetyltransferase. The acetylation of this protein inhibits the initiation of DNA replication and cell cycle progression. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4172 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 156 total — 1 pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 85.2% of screened cell lines
• MANE Select transcript: NM_002388

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6945
Approved symbol	MCM3
Name	minichromosome maintenance complex component 3
Location	6p12.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000112118
Ensembl biotype	protein_coding
OMIM	602693
Entrez	4172

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 26 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000229854, ENST00000419835, ENST00000421471, ENST00000476448, ENST00000596288, ENST00000616552, ENST00000860054, ENST00000860055, ENST00000860056, ENST00000860057, ENST00000860058, ENST00000860059, ENST00000860060, ENST00000939871, ENST00000939872, ENST00000939873, ENST00000939874, ENST00000939875, ENST00000939876, ENST00000939877, ENST00000939878, ENST00000939879, ENST00000939880, ENST00000939881, ENST00000939882, ENST00000939883, ENST00000946802

RefSeq mRNA: 9 — MANE Select: NM_002388 NM_001270472, NM_001366369, NM_001366370, NM_001366371, NM_001366372, NM_001366373, NM_001366374, NM_001366375, NM_002388

CCDS: CCDS4940, CCDS75468

Canonical transcript exons

ENST00000596288 — 17 exons

Exon	Start	End
ENSE00000756141	52266075	52266144
ENSE00000756145	52269086	52269226
ENSE00000756147	52272301	52272451
ENSE00000756148	52273230	52273356
ENSE00000850466	52266611	52266696
ENSE00001015139	52267865	52267968
ENSE00001916350	52264015	52264786
ENSE00002510915	52273742	52273916
ENSE00002524738	52276268	52276476
ENSE00002530589	52279361	52279599
ENSE00003160088	52284597	52284742
ENSE00003486722	52277535	52277688
ENSE00003493401	52282653	52282861
ENSE00003505305	52283294	52283406
ENSE00003604841	52277067	52277198
ENSE00003604938	52282045	52282175
ENSE00003627487	52278742	52278850

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 97.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 42.8792 / max 407.8895, expressed in 1787 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73956	42.8090	1787
73954	0.0702	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	97.24	gold quality
embryo	UBERON:0000922	96.12	gold quality
ganglionic eminence	UBERON:0004023	94.80	gold quality
mucosa of transverse colon	UBERON:0004991	94.08	gold quality
vermiform appendix	UBERON:0001154	93.68	gold quality
rectum	UBERON:0001052	93.30	gold quality
caecum	UBERON:0001153	93.28	gold quality
lymph node	UBERON:0000029	93.20	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.64	gold quality
endometrium epithelium	UBERON:0004811	92.01	gold quality
trabecular bone tissue	UBERON:0002483	91.89	gold quality
body of uterus	UBERON:0009853	91.53	gold quality
bone marrow	UBERON:0002371	91.44	gold quality
secondary oocyte	CL:0000655	91.35	gold quality
calcaneal tendon	UBERON:0003701	91.25	gold quality
esophagus mucosa	UBERON:0002469	90.85	gold quality
thymus	UBERON:0002370	90.76	gold quality
smooth muscle tissue	UBERON:0001135	90.75	gold quality
ectocervix	UBERON:0012249	90.75	gold quality
granulocyte	CL:0000094	90.69	gold quality
spleen	UBERON:0002106	90.57	gold quality
esophagus	UBERON:0001043	90.41	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.39	gold quality
oocyte	CL:0000023	90.28	gold quality
right ovary	UBERON:0002118	90.28	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.14	gold quality
lower esophagus	UBERON:0013473	90.12	gold quality
popliteal artery	UBERON:0002250	90.08	gold quality
tibial artery	UBERON:0007610	90.07	gold quality
apex of heart	UBERON:0002098	90.04	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-MTAB-6075	yes	584.74
E-GEOD-93593	yes	555.51
E-ENAD-20	yes	504.58
E-GEOD-75140	yes	500.10
E-GEOD-99795	yes	324.64
E-MTAB-10485	yes	269.71
E-CURD-114	yes	249.29
E-MTAB-7037	yes	247.66
E-MTAB-11121	yes	232.88
E-MTAB-8530	yes	197.13
E-MTAB-10290	yes	165.59
E-MTAB-9067	yes	20.26
E-HCAD-10	yes	16.67
E-ANND-3	yes	9.45
E-GEOD-76312	no	527.72

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, E2F4, E2F6, MYCN

miRNA regulators (miRDB)

48 targeting MCM3, 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-10401-5P	99.99	65.79	948
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-106A-3P	99.53	67.58	995
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-12123	99.52	71.79	2990

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 85.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• The MCM3 acetylase MCM3AP inhibits initiation, but not elongation, of DNA replication via interaction with this protein (PMID:12226073)
• 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)
• Elevated MCM3 protein expression is associated with neoplasms (PMID:15623617)
• MCM3 is overexpressed in human astrocytic tumors and elicits a cancer-restricted humoral immune response in some patients with brain neoplasms (PMID:15671553)
• purified hRad51 and hRad52 interact with each other as well as with Mini chromosome maintenance (MCM) proteins in HeLa cell extracts (PMID:15766559)
• ORC1 and Mcm3 proteins are required for DNA replication in protein extracts from human cells (PMID:16537544)
• analysis of carboxyl-terminal MCM3 phosphorylation sites and their motifs (PMID:17244605)
• These data reveal that CDK-dependent MCM3 phosphorylation contributes to the regulated formation of the MCM2-7 complex. (PMID:18524952)
• MCM3 may be a more reliable proliferation marker than Ki-67 in accessing the growth of tumor and evaluating tumor aggressiveness of papillary thyroid carcinoma. (PMID:19818763)
• Using U373MG cells we found that HCMV IE86 protein was bound to Mcm3, but did not inhibit the cellular DNA synthesis. (PMID:20545442)
• deregulation of MCM2, MCM3 and MCM7 expression might be involved in medulloblastoma tumorigenesis (PMID:20661220)
• MCM3 gene expression is decreased in follicular variant of papillary thyroid carcinoma, contrary to expectation. (PMID:21509594)
• excess of MCM3 up-regulates the phosphorylation of CHK1 Ser-345 and CDK2 Thr-14. (PMID:21965652)
• These findings provide validation of the utility of MCM3 expression as an independent biomarker for prognostication of patients with primary melanoma (PMID:22805320)
• Mcm2-7 loads onto origins during initiation as a double hexamer, yet does not act as a double-stranded DNA pump during elongation. (PMID:22918583)
• Relatively lower MCM3 protein expression in follicular variant of papillary thyroid carcinoma comparing to classical type could be due to a different tumorigenic pathway favored in this type of tissue. (PMID:23821456)
• The relatively lower MCM3 protein expression in FVPTC. (PMID:23821456)
• High MCM3 expression is associated with mucoepidermoid carcinomas and adenoid cystic carcinomas in salivary gland tumors. (PMID:23886132)
• present study aimed to investigate the relationship between expression of minichromosome maintenance proteins (MCM-3, MCM-7), metallothioneins (MT-I/II, MT-III), and Ki-67 in 103 ovarian cancer cases, mostly of the serous histological type (PMID:24324072)
• Expression of KB cell MCM3 was not affected by doxorubicin. (PMID:24344040)
• Of the total, the deregulation of several genes (CDK1, CDK2, CDK4, MCM2, MCM3, MCM4, EIF3a and RPN2) were potentially associated with disease development and progression. (PMID:24386425)
• Results show that in Glioma patients, MCM 2, MCM3 and MCM7 mRNA are up-regulated and correlated with poor outcome. (PMID:25046975)
• normal DNA replication and replication checkpoint activation is regulated through the novel phosphorylation of MCM3 by Chk1 (PMID:25809478)
• High MCM-3 expression correlated with Cutaneous T-cell Lymphomas. (PMID:26504025)
• reveal the Minichromosome Maintenance Complex to be a critical and directly regulated node within the miR-183 signaling network in MYCN-amplified neuroblastoma cells. Randomly selected MCMs 3 and 5 were experimentally confirmed as direct targets of miR-183. (PMID:27239679)
• this study shows that MCM3 is a novel proliferation marker in oral squamous cell carcinoma (PMID:27258565)
• The aim of this study is to analyze the immunoexpression of Ki67, p53, MCM3 and PCNA markers in epithelial remnants of dental follicles of impacted teeth and to identify a possible correlation between the immunoexpression of these markers in dentigerous cysts and keratocystic odontogenic tumors. (PMID:27516012)
• These data establish new functions for KEAP1 within the nucleus and identify MCM3 as a novel substrate of the KEAP1-CUL3-RBX1 E3 ligase. (PMID:27621311)
• High MCM3 expression is associated with bone metastasis and advanced human prostate cancer. (PMID:28424404)
• the decreased growth of osteosarcoma cells by MCM2 or MCM3 knockdown was reversed by DHX9 overexpression, indicating that MCM2 and MCM3 activity was DHX9-dependent. (PMID:28460433)
• The results of our preliminary study emphasize the need for future research on MCM-3 as a sensitive proliferation marker, providing an alternative to Ki-67, in cases of various major salivary gland epithelial tumors in children and adolescents. (PMID:28547962)
• Study characterize the interaction of Keap1, a central antioxidant response regulator in Metazoa, with the replicative helicase subunit protein MCM3. Analysis suggests that structural determinants of the interaction of Keap1 with its critical downstream target - Nrf2 master transactivator of oxidative stress response genes - may have evolved in evolution to mimic the conserved helix-2-insert motif of MCM3. (PMID:30108253)
• Data report that MCM3 is a novel target of Pin1 through directly interacting with Pin1 WW domain. Proline-directed phosphorylation of MCM3 at S112 and T722 are crucial for the interaction with Pin1. MCM3 as a subunit of the MCM2-7 heterocomplex is part of the pre-replication complex responsible for replication licensing and is implicated in the formation of the replicative helicase during the replication progression. (PMID:30316783)
• Ki-67, MCM-3, and MCM-7, but not MCM-5 are reliable proliferative and diagnostic markers in discerning benign and malignant adrenocortical tumors. (PMID:30842144)
• PLK1 promotes proliferation and suppresses apoptosis of renal cell carcinoma cells by phosphorylating MCM3. (PMID:31186514)
• Results show that found DNA replication initiation protein MCM3 was upregulated in hepatocellular carcinoma (HCC) tissues and cells and its expression correlated with poor outcome and radioresistance. MCM3 promoted radioresistance through activating NF-kappaB pathway, strengthening the role of MCM subunits in the tumor progression. These Findings revealed an independent prognostic factor of MCM3 for HCC. (PMID:31208444)
• Gene expression profiling revealed MCM3 to be a better marker than Ki67 in prognosis of invasive ductal breast carcinoma patients. (PMID:31980982)
• Elevated expression of minichromosome maintenance 3 indicates poor outcomes and promotes G1/S cell cycle progression, proliferation, migration and invasion in colorectal cancer. (PMID:32597491)
• MCM3 proliferative index is worthier over Ki-67 in the characterization of salivary gland tumors. (PMID:33433405)
• MCM complex members MCM3 and MCM7 are associated with a phenotypic spectrum from Meier-Gorlin syndrome to lipodystrophy and adrenal insufficiency. (PMID:33654309)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mcm3	ENSDARG00000024204
mus_musculus	Mcm3	ENSMUSG00000041859
rattus_norvegicus	Mcm3	ENSRNOG00000012543
drosophila_melanogaster	Mcm3	FBGN0284442
caenorhabditis_elegans		WBGENE00003155

Paralogs (8): MCM2 (ENSG00000073111), MCM6 (ENSG00000076003), MCM5 (ENSG00000100297), MCM4 (ENSG00000104738), MCM9 (ENSG00000111877), MCM8 (ENSG00000125885), MCM7 (ENSG00000166508), MCMDC2 (ENSG00000178460)

Protein

Protein identifiers

DNA replication licensing factor MCM3 — P25205 (reviewed: P25205)

Alternative names: DNA polymerase alpha holoenzyme-associated protein P1, P1-MCM3, RLF subunit beta, p102

All UniProt accessions (5): P25205, A0A0S2Z4T1, A0A499FHX9, J3KQ69, Q7Z6P5

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.

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. Associated with the replication-specific DNA polymerase alpha. Interacts with MCMBP. Interacts with ANKRD17. Interacts with MCM3AP isoform MCM3AP; this interaction leads to MCM3 acetylation.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. Acetylated by MCM3AP. O-glycosylated (O-GlcNAcylated), in a cell cycle-dependent manner.

Miscellaneous. Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. The MCM2-7 hexamer is the proposed physiological active complex.

Similarity. Belongs to the MCM family.

Isoforms (2)

UniProt ID	Names	Canonical?
P25205-1	1	yes
P25205-2	2

RefSeq proteins (9): NP_001257401, NP_001353298, NP_001353299, NP_001353300, NP_001353301, NP_001353302, NP_001353303, NP_001353304, NP_002379* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001208	MCM_dom	Domain
IPR003593	AAA+_ATPase	Domain
IPR008046	Mcm3	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
IPR056575	WH_MCM3_C	Domain

Pfam: PF00493, PF14551, PF17207, PF17855, PF23191

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (103 total): strand 25, helix 24, modified residue 18, turn 10, binding site 7, sequence variant 6, compositionally biased region 3, short sequence motif 2, initiator methionine 1, chain 1, site 1, domain 1, region of interest 1, splice variant 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

28 structures.

PDB	Method	Resolution (Å)
7W1Y	ELECTRON MICROSCOPY	2.59
9E2Z	ELECTRON MICROSCOPY	2.6
7PLO	ELECTRON MICROSCOPY	2.8
8W0F	ELECTRON MICROSCOPY	2.8
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
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
9LXE	ELECTRON MICROSCOPY	3.96
9VLW	ELECTRON MICROSCOPY	4.06
8S0F	ELECTRON MICROSCOPY	4.1
9C6G	ELECTRON MICROSCOPY	4.26
7W68	ELECTRON MICROSCOPY	4.4
8RWV	ELECTRON MICROSCOPY	6.68
6XTY	ELECTRON MICROSCOPY	6.77

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P25205-F1	74.04	0.09

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): 478 (arginine finger)

Ligand- & substrate-binding residues (7): 393; 394; 395; 397; 523; 664; 353

Post-translational modifications (18): 2, 160, 275, 293, 535, 547, 611, 668, 672, 674, 681, 708, 711, 713, 722, 725, 728, 734

Mutagenesis-validated functional residues (1):

Position	Phenotype
535	50% reduction in phosphorylation by atm or atr.

Function

Pathways and Gene Ontology

Reactome pathways

17 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-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

MSigDB gene sets: 445 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GNF2_CKS1B, E2F_Q4, MORF_DNMT1, WU_APOPTOSIS_BY_CDKN1A_VIA_TP53, REACTOME_DNA_REPLICATION, MODULE_52, E2F_Q4_01, GNF2_MSH2, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, MORF_ESPL1, GNF2_CENPF, E2F4DP1_01, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, KAAB_FAILED_HEART_ATRIUM_DN

GO Biological Process (6): double-strand break repair via break-induced replication (GO:0000727), DNA replication (GO:0006260), DNA replication initiation (GO:0006270), DNA strand elongation involved in DNA replication (GO:0006271), regulation of DNA-templated DNA replication initiation (GO:0030174), mitotic DNA replication initiation (GO:1902975)

GO Molecular Function (10): DNA binding (GO:0003677), DNA helicase activity (GO:0003678), single-stranded DNA binding (GO:0003697), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), nucleotide binding (GO:0000166), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787), single-stranded DNA helicase activity (GO:0017116)

GO Cellular Component (10): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), alpha DNA polymerase:primase complex (GO:0005658), membrane (GO:0016020), MCM complex (GO:0042555), perinuclear region of cytoplasm (GO:0048471), CMG complex (GO:0071162), chromosome (GO:0005694), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-12 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
Mitotic G1 phase and G1/S transition	1
S Phase	1
Cell Cycle Checkpoints	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
DNA metabolic process	2
DNA-templated DNA replication	2
ATP-dependent activity	2
double-strand break repair via homologous recombination	1
DNA biosynthetic process	1
DNA replication	1
DNA strand elongation	1
DNA synthesis involved in DNA replication	1
DNA replication initiation	1
regulation of DNA-templated DNA replication	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
DNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate 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
catalytic activity	1
DNA helicase activity	1
chromosomal region	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
DNA polymerase complex	1
nuclear replisome	1
nuclear DNA-directed RNA polymerase complex	1
protein-containing complex	1
MCM core complex	1
cytoplasm	1
nuclear chromosome	1
GINS complex	1
DNA replication preinitiation complex	1

Protein interactions and networks

STRING

3135 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCM3	CDC6	Q99741	993
MCM3	MCM5	P33992	991
MCM3	MCM4	P33991	991
MCM3	MCM6	Q14566	991
MCM3	MCM7	P33993	990
MCM3	CDC45	O75419	974
MCM3	MCM3AP	O60318	971
MCM3	MCM10	Q7L590	939
MCM3	CDT1	Q9H211	936
MCM3	CDC7	O00311	928
MCM3	MCMBP	Q9BTE3	915
MCM3	DBF4	Q9UBU7	891
MCM3	ORC5	O43913	823
MCM3	ORC3	Q9UBD5	813
MCM3	GINS3	Q9BRX5	811

IntAct

237 interactions, top by confidence:

A	B	Type	Score
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
MCMBP	MCM3	psi-mi:“MI:0914”(association)	0.890
MCMBP	MCM3	psi-mi:“MI:0915”(physical association)	0.890
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
MCM5	MCM3	psi-mi:“MI:0407”(direct interaction)	0.850
MCM3	MCM5	psi-mi:“MI:0914”(association)	0.850
MCM3	MCM5	psi-mi:“MI:0915”(physical association)	0.850
MCM5	MCM3	psi-mi:“MI:0914”(association)	0.850
MCM6	MCM3	psi-mi:“MI:0914”(association)	0.810
MCM7	MCM3	psi-mi:“MI:0914”(association)	0.810
MCM3	MCM6	psi-mi:“MI:0407”(direct interaction)	0.810
MCM3	MCM7	psi-mi:“MI:0914”(association)	0.810
CDK19	MED19	psi-mi:“MI:0914”(association)	0.770
CEP19	CEP43	psi-mi:“MI:0914”(association)	0.770
PPP2R1B	STRN	psi-mi:“MI:0914”(association)	0.730
PRKAG2	PRKAB2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ZRANB3	PCNA	psi-mi:“MI:0914”(association)	0.600
MCM2	CDC45	psi-mi:“MI:0914”(association)	0.570

BioGRID (581): MCM3 (Affinity Capture-MS), MCM3 (Affinity Capture-MS), MCM3 (Affinity Capture-MS), MCM3 (Affinity Capture-MS), MCM3 (Affinity Capture-MS), MCM3 (Affinity Capture-MS), MCM3 (Reconstituted Complex), GINS4 (Co-fractionation), HNRNPF (Co-fractionation), HNRNPH2 (Co-fractionation), HNRNPH3 (Co-fractionation), MCFD2 (Co-fractionation), MCM2 (Co-fractionation), MCM3 (Co-fractionation), MCM3 (Co-fractionation)

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

7 interactions.

A	Effect	B	Mechanism
ATM	unknown	MCM3	phosphorylation
DAPK1	unknown	MCM3	phosphorylation
CDK2	up-regulates	MCM3	phosphorylation
CyclinE/CDK2	up-regulates	MCM3	phosphorylation
MCM3	“form complex”	MCM	binding
YAP1	“up-regulates quantity by expression”	MCM3	“transcriptional regulation”
YAP/TAZ	“up-regulates quantity by expression”	MCM3	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 226 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	14	29.3×	8e-15
Activation of ATR in response to replication stress	13	25.0×	5e-13
G1/S Transition	15	22.4×	3e-14
DNA Replication Pre-Initiation	11	22.4×	1e-10
DNA Replication	13	19.8×	9e-12
Switching of origins to a post-replicative state	10	19.3×	6e-09
Synthesis of DNA	10	19.3×	6e-09
Mitotic G1 phase and G1/S transition	15	17.7×	7e-13

GO biological processes:

GO term	Partners	Fold	FDR
regulation of DNA-templated DNA replication initiation	6	31.6×	7e-06
DNA replication initiation	10	31.2×	5e-10
DNA replication	9	7.4×	1e-03
protein phosphorylation	18	6.1×	5e-07
DNA damage response	15	4.0×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	124
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
916002	GRCh37/hg19 6p12.3-12.2(chr6:51695623-52371918)	Pathogenic

SpliceAI

2578 predictions. Top by Δscore:

Variant	Effect	Δscore
6:52264784:AACCT:A	acceptor_loss	1.0000
6:52264786:CCT:C	acceptor_loss	1.0000
6:52264787:C:CA	acceptor_loss	1.0000
6:52264793:C:CT	acceptor_gain	1.0000
6:52264793:C:T	acceptor_gain	1.0000
6:52264794:A:T	acceptor_gain	1.0000
6:52264797:C:CT	acceptor_gain	1.0000
6:52264798:A:T	acceptor_gain	1.0000
6:52266155:T:TC	acceptor_gain	1.0000
6:52266158:A:AC	acceptor_gain	1.0000
6:52266158:A:C	acceptor_gain	1.0000
6:52266162:T:C	acceptor_gain	1.0000
6:52266162:T:TC	acceptor_gain	1.0000
6:52266164:G:GC	acceptor_gain	1.0000
6:52266170:A:AC	acceptor_gain	1.0000
6:52266170:A:C	acceptor_gain	1.0000
6:52266607:TCAC:T	donor_loss	1.0000
6:52266608:CACCT:C	donor_loss	1.0000
6:52266609:ACCT:A	donor_loss	1.0000
6:52266610:C:CT	donor_loss	1.0000
6:52266707:C:CT	acceptor_gain	1.0000
6:52266707:C:T	acceptor_gain	1.0000
6:52266710:A:T	acceptor_gain	1.0000
6:52266712:CAGT:C	acceptor_gain	1.0000
6:52266713:A:T	acceptor_gain	1.0000
6:52267862:TA:T	donor_loss	1.0000
6:52267864:C:CT	donor_loss	1.0000
6:52267864:CCT:C	donor_gain	1.0000
6:52267966:AACC:A	acceptor_loss	1.0000
6:52267967:ACC:A	acceptor_loss	1.0000

AlphaMissense

5322 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:52273789:A:T	V501D	1.000
6:52273854:A:C	F479L	1.000
6:52273854:A:T	F479L	1.000
6:52273856:A:G	F479L	1.000
6:52273887:G:C	N468K	1.000
6:52273887:G:T	N468K	1.000
6:52276281:G:T	P454H	1.000
6:52276283:G:C	N453K	1.000
6:52276283:G:T	N453K	1.000
6:52276285:T:C	N453D	1.000
6:52276288:C:G	A452P	1.000
6:52276299:A:T	V448D	1.000
6:52276304:G:C	C446W	1.000
6:52276311:G:T	A444D	1.000
6:52276375:G:C	H423D	1.000
6:52276414:C:T	E410K	1.000
6:52276416:T:A	D409V	1.000
6:52276421:G:C	C407W	1.000
6:52277087:A:T	V382D	1.000
6:52277093:G:T	A380D	1.000
6:52277099:A:G	L378P	1.000
6:52277099:A:T	L378Q	1.000
6:52277123:C:T	G370D	1.000
6:52277168:A:G	L355P	1.000
6:52277177:G:A	S352F	1.000
6:52277178:A:G	S352P	1.000
6:52277179:C:A	K351N	1.000
6:52277179:C:G	K351N	1.000
6:52277181:T:G	K351Q	1.000
6:52277183:G:T	A350D	1.000

dbSNP variants (sampled 300 via entrez): RS1000064305 (6:52272350 T>C), RS1000316889 (6:52263515 G>A), RS1000335077 (6:52266621 TTCC>T), RS1000378443 (6:52269805 T>C), RS1000406926 (6:52278838 A>C), RS1000473313 (6:52269530 T>C), RS1000512618 (6:52282693 G>A,T), RS1000556403 (6:52275556 T>G), RS1000632544 (6:52281082 G>A), RS1000648354 (6:52282933 C>T), RS1000684604 (6:52281303 T>G), RS1000908211 (6:52275213 T>C), RS1001058960 (6:52271212 G>A), RS1001319828 (6:52285263 A>C,G), RS1001382332 (6:52270978 C>A)

Disease associations

OMIM: gene MIM:602693 | disease phenotypes: MIM:224690

GenCC curated gene-disease

Mondo (2): Meier-Gorlin syndrome (MONDO:0016817), autosomal recessive polycystic kidney disease (MONDO:0009889)

Orphanet (3): Ear-patella-short stature syndrome (Orphanet:2554), Autosomal recessive polycystic kidney disease (Orphanet:731), (Orphanet:8378)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST011681_6	Cryptococcosis in HIV infection	8.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538012	Meier-Gorlin syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630813 (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
7.54	Kd	28.92	nM	CHEMBL5653589
7.54	ED50	28.92	nM	CHEMBL5653589
6.50	Kd	312.5	nM	CHEMBL3752910
6.50	ED50	312.5	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 13 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	2148731: Binding affinity to human MCM3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0289	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148731: Binding affinity to human MCM3 incubated for 45 mins by Kinobead based pull down assay	kd	0.3125	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	6
sodium arsenite	decreases expression, increases abundance, increases expression	4
Benzo(a)pyrene	decreases expression, increases expression	3
Estradiol	increases expression	3
Cyclosporine	decreases expression	3
trichostatin A	decreases expression	2
cobaltous chloride	decreases expression	2
Copper	decreases expression, affects binding	2
Fluorouracil	decreases expression, affects reaction	2
Lead	affects expression, decreases expression	2
Mustard Gas	decreases expression, increases phosphorylation	2
Tretinoin	decreases expression	2
Aflatoxin B1	decreases expression, increases expression	2
Cadmium Chloride	decreases expression	2
tert-Butylhydroperoxide	affects expression, decreases expression	2
Vitamin K 3	affects expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
diminazene aceturate	decreases expression	1
triphenyl phosphate	affects expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
methylselenic acid	decreases expression	1
decabromobiphenyl ether	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
nonylphenol	increases expression	1
manganese chloride	decreases expression, increases abundance	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4605090	Binding	Induction of ubiquitination of MCM3 in human NCI-H1975 cells incubated for 24 hrs by immunoblot analysis (Rvb = 1 No_unit)	Suppression of Drug-Resistant Non-Small-Cell Lung Cancer with Inhibitors Targeting Minichromosomal Maintenance Protein. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04782258	PHASE3	RECRUITING	A Study to See Iftolvaptan is Safe in Infants and Children Who at Enrollment Are 28 Days to Less Than 18 Years Old withAutosomal Recessive Polycystic Kidney Disease (ARPKD)
NCT04786574	PHASE3	WITHDRAWN	A Study to See if Tolvaptan Can Delay Dialysis in Infants and Children Who at Enrollment Are 28 Days to Less Than 12 Weeks Old With Autosomal Recessive Polycystic Kidney Disease (ARPKD)
NCT04569149	Not specified	RECRUITING	Primordial Dwarfism Registry
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT06147414	Not specified	RECRUITING	Development of Non-Invasive Prenatal Diagnosis for Single Gene Disorders
NCT07201025	Not specified	RECRUITING	Imaging Assessments of ARPKD Kidney Disease Progression