MCM4

Summary

MCM4 (minichromosome maintenance complex component 4, HGNC:6947) is a protein-coding gene on chromosome 8q11.21, encoding DNA replication licensing factor MCM4 (P33991). 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 common-essential gene (DepMap: required in 98.4% of cancer cell lines).

The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for 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. The MCM complex consisting of this protein and MCM2, 6 and 7 proteins possesses DNA helicase activity, and may act as a DNA unwinding enzyme. The phosphorylation of this protein by CDC2 kinase reduces the DNA helicase activity and chromatin binding of the MCM complex. This gene is mapped to a region on the chromosome 8 head-to-head next to the PRKDC/DNA-PK, a DNA-activated protein kinase involved in the repair of DNA double-strand breaks. Alternatively spliced transcript variants encoding the same protein have been reported.

Source: NCBI Gene 4173 — RefSeq curated summary.

At a glance

• Gene–disease (curated): primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency (Strong, GenCC)
• GWAS associations: 9
• Clinical variants (ClinVar): 720 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 98.4% of screened cell lines (common-essential)
• MANE Select transcript: NM_182746

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6947
Approved symbol	MCM4
Name	minichromosome maintenance complex component 4
Location	8q11.21
Locus type	gene with protein product
Status	Approved
Aliases	CDC54, hCdc21, P1-Cdc21, MGC33310
Ensembl gene	ENSG00000104738
Ensembl biotype	protein_coding
OMIM	602638
Entrez	4173

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 19 protein_coding, 11 retained_intron, 5 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000262105, ENST00000517709, ENST00000518221, ENST00000518382, ENST00000518680, ENST00000519138, ENST00000519170, ENST00000519470, ENST00000520637, ENST00000520994, ENST00000521151, ENST00000521261, ENST00000523853, ENST00000524086, ENST00000647877, ENST00000648407, ENST00000648519, ENST00000648533, ENST00000648554, ENST00000649838, ENST00000649919, ENST00000649973, ENST00000650216, ENST00000650327, ENST00000697120, ENST00000697121, ENST00000697122, ENST00000697123, ENST00000884671, ENST00000884672, ENST00000884673, ENST00000884674, ENST00000936717, ENST00000936718, ENST00000936719, ENST00000936720, ENST00000936721, ENST00000936722

RefSeq mRNA: 2 — MANE Select: NM_182746 NM_005914, NM_182746

CCDS: CCDS6143

Canonical transcript exons

ENST00000649973 — 17 exons

Exon	Start	End
ENSE00000693380	47962053	47962216
ENSE00000693401	47966187	47966407
ENSE00000693404	47967365	47967485
ENSE00000693414	47971341	47971468
ENSE00000693417	47972857	47973064
ENSE00000693420	47975715	47975848
ENSE00002123614	47976686	47978160
ENSE00002733163	47961131	47961214
ENSE00003323524	47974734	47974962
ENSE00003469030	47969798	47970057
ENSE00003484202	47962305	47962406
ENSE00003540221	47962945	47963040
ENSE00003548000	47961516	47961680
ENSE00003652723	47970511	47970876
ENSE00003683573	47964574	47964712
ENSE00003690917	47962764	47962859
ENSE00003969591	47960941	47961014

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 99.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 65.4412 / max 797.9968, expressed in 1798 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88778	61.9143	1792
88777	2.6887	1173
205177	0.3685	182
88780	0.2385	117
88779	0.2312	109

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.05	gold quality
ganglionic eminence	UBERON:0004023	98.11	gold quality
embryo	UBERON:0000922	97.05	gold quality
bone marrow cell	CL:0002092	94.47	gold quality
left testis	UBERON:0004533	93.79	gold quality
cortical plate	UBERON:0005343	93.56	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.45	gold quality
right testis	UBERON:0004534	93.40	gold quality
penis	UBERON:0000989	93.37	gold quality
testis	UBERON:0000473	93.31	gold quality
bone marrow	UBERON:0002371	93.04	gold quality
stromal cell of endometrium	CL:0002255	92.68	gold quality
buccal mucosa cell	CL:0002336	92.15	gold quality
colonic epithelium	UBERON:0000397	91.91	gold quality
oocyte	CL:0000023	91.86	gold quality
vermiform appendix	UBERON:0001154	91.64	gold quality
mucosa of transverse colon	UBERON:0004991	91.60	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.47	gold quality
trabecular bone tissue	UBERON:0002483	91.42	gold quality
endometrium epithelium	UBERON:0004811	91.38	gold quality
rectum	UBERON:0001052	91.09	gold quality
esophagus mucosa	UBERON:0002469	90.62	gold quality
sperm	CL:0000019	90.59	gold quality
adrenal tissue	UBERON:0018303	90.49	gold quality
caecum	UBERON:0001153	90.40	gold quality
pharyngeal mucosa	UBERON:0000355	89.81	gold quality
skin of abdomen	UBERON:0001416	89.64	gold quality
tonsil	UBERON:0002372	89.52	gold quality
skin of leg	UBERON:0001511	89.38	gold quality
male germ cell	CL:0000015	89.14	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	910.60
E-ENAD-20	yes	871.34
E-MTAB-7052	yes	231.64
E-MTAB-10662	yes	195.38
E-MTAB-10290	yes	168.37
E-ANND-3	yes	7.79
E-MTAB-6911	no	798.96
E-MTAB-6142	no	712.30
E-MTAB-7008	no	585.88
E-GEOD-76312	no	407.34

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYB, MYCN

miRNA regulators (miRDB)

52 targeting MCM4, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-140-5P	99.44	67.20	792
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-4460	99.37	68.52	615
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-4796-3P	99.08	68.38	1681

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 34)

• the phosphorylation of MCM4 in the checkpoint control inhibits DNA replication, which includes blockage of DNA fork progression, through inactivation of the MCM complex (PMID:12714602)
• HU- or UV irradiation-stimulated phosphorylation of MCM4 at several CDK sites led to inhibition of MCM4 helicase activity, consistent with the notion that the phosphorylation of MCM4 is involved in regulation of DNA synthesis in the checkpoint control. (PMID:15037254)
• These results suggest that phosphorylation of MCM4 has several distinct and site-specific roles in the function of MCM during the mammalian cell cycle. (PMID:16519687)
• Expression of EBV-protein kinase caused phosphorylation of Thr-19 & Thr-110 on MCM4 (PMID:17005684)
• MCM4 phosphorylation by Cdc7 kinase facilitates its interaction with Cdc45 on chromatin (PMID:17046832)
• The positive rate of MCM4 was significantly higher in stage T3 than in stage T1 esophageal cancer. (PMID:17222376)
• Data show that two fragments (148-441 and 442-676) from the central region of MCM2 were mainly responsible for the interaction between MCM2 and MCM4, and this was revealed by a pulldown analysis using MCM4 protein beads. (PMID:18190532)
• Sequence alignment of archaeal MCMs and MCM4 from Homo sapiens and Saccharomyces cerevisiae shows that Aeropyrum pernix MCM shares 32% identity with human and yeast MCM4. (PMID:19053250)
• the ability of cytomegalovirus to delay the accumulation of the mini-chromosome maintenance (MCM) complex proteins, represented by MCM2 and MCM4, and prevent their loading onto chromatin, was compromised in the absence of pUL117 (PMID:20333247)
• MCM4 did not predict patient survival in this series of cutaneous melanomas. (PMID:20398247)
• higher expression in non-small cell lung cancer (PMID:20884074)
• Widdrol breaks DNA directly in HT29 cells, resulting in checkpoint activation via Chk2-p53-Cdc25A-p21-MCM4 pathway and finally cells go to G1-phase cell cycle arrest and apoptosis. (PMID:22160829)
• partial MCM4 deficiency results in a genetic syndrome of growth retardation with adrenal insufficiency and selective NK deficiency (PMID:22354167)
• MCM4 mutation may have a role in adrenal failure, short stature, and natural killer cell deficiency (PMID:22354170)
• Mutations in MCM4/PRKDC represent a novel cause of DNA breakage and NK cell deficiency. (PMID:22499342)
• point mutation of MCM4 perturbs proper interaction with MCM6 to affect complex formation of MCM4/6/7 that is a core structure of MCM2-7 complex (PMID:22668557)
• 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)
• Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta) protein attenuates vascular lesion formation by inhibition of chromatin loading of minichromosome maintenance complex in smooth muscle cells (PMID:23264620)
• 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)
• Purified MCM4/6/7 complex containing the G364R MCM4 exhibited similar levels of single-stranded DNA binding and ATPase activities to the complex containing wild-type MCM4 (PMID:25661590)
• Mutant p53 depletion profoundly influenced PARP1 localization and increased the level of PCNA and MCM4 proteins. (PMID:25733866)
• We did not find any evidence of augmented response to a short-term (48 h) cisplatin treatment in these MCM4-deficient cells. However, MCM4-/HPV16+ SiHa cells cannot withstand a prolonged treatment (up to 5 days) of even a sublethal dosage of cisplatin (PMID:26188903)
• MCM4 and MCM7 expression is significantly correlated with Ki-67, Bmi1, and cyclin E expression in esophageal adenocarcinoma, squamous cell carcinoma and precancerous lesions. (PMID:27476776)
• This MCM4 mutation affected human MCM4/6/7 complex formation, since the complex containing the mutant MCM4 protein is unstable and the mutant MCM4 protein is tend to be degraded. (PMID:27794528)
• siRNA of MCM4 inhibits proliferation and induces apoptosis of laryngeal squamous cell carcinoma (LSCC) cell line UMSCC 5. MCM4 mRNA is overexpressed in carcinoma tissues and correlates with male gender, smoking history and poor differentiation in Chinese LSCC patients. (PMID:29135113)
• Data suggest that MCM4 phosphorylation by CDK2 plays role in DNA replication licensing system MCM4/MCM6/MCM7; this phosphorylation interferes with MCM complex function by lowering stability of MCM complex; MCM4 is highly phosphorylated in S phase. (MCM = minichromosome maintenance complex [hexamer of components 4/6/7]; CDK2 = cyclin-dependent kinase-2) (PMID:30184107)
• MCM4, MCM5, and MCM8 may have roles in lung adenocarcinoma prognosis with roles in regulating the cell cycle, DNA replication and other multiple biological processes and pathways (PMID:31323040)
• MCM2, MCM4, and MCM6 labeling seems to outperform Ki67 as tools to assess cellular proliferation in breast cancer. The onset of sustained Ki67 expression occurs only in late G1 phase, while MCM can label all proliferative cells during the active phases of cell cycle (PMID:31476594)
• High MCM4 expression is associated with lung adenocarcinoma. (PMID:31545501)
• MCM4 in human hepatocellular carcinoma: a potent prognostic factor associated with cell proliferation. (PMID:33716256)
• Identification of MCM4 as a Prognostic Marker of Hepatocellular Carcinoma. (PMID:34961841)
• Minichromosome Maintenance 4 Is Associated with Cancer Stemness and Poor Survival of Patients with Gastric Cancer. (PMID:35830849)
• Identification of MCM4 and PRKDC as new regulators of osteosarcoma cell dormancy based on 3D cell cultures. (PMID:38216092)
• MCM4 potentiates evasion of hepatocellular carcinoma from sorafenib-induced ferroptosis through Nrf2 signaling pathway. (PMID:39276458)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mcm4	ENSDARG00000040041
mus_musculus	Mcm4	ENSMUSG00000022673
rattus_norvegicus	Mcm4	ENSRNOG00000001833
drosophila_melanogaster	dpa	FBGN0015929
caenorhabditis_elegans	mcm-4	WBGENE00003156

Paralogs (8): MCM2 (ENSG00000073111), MCM6 (ENSG00000076003), MCM5 (ENSG00000100297), MCM9 (ENSG00000111877), MCM3 (ENSG00000112118), MCM8 (ENSG00000125885), MCM7 (ENSG00000166508), MCMDC2 (ENSG00000178460)

Protein

Protein identifiers

DNA replication licensing factor MCM4 — P33991 (reviewed: P33991)

Alternative names: CDC21 homolog, P1-CDC21

All UniProt accessions (13): A0A3B3IRR8, A0A3B3IS57, A0A3B3IS88, A0A3B3ISC1, A0A3B3IT92, A0A3B3ITP6, A0A3B3IU45, A0A8V8TKP2, E5RFR3, E5RG31, E5RG53, E5RHP5, P33991

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.

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 MCMBP.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. Sumoylated; SUMO2 modified in response to stress caused by inhibition of proteasome activity (in vitro).

Disease relevance. Immunodeficiency 54 (IMD54) [MIM:609981] An autosomal recessive disorder characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased numbers of natural killer cells, and recurrent viral infections, most often affecting the respiratory tract and leading to respiratory failure. Affected individuals also have adrenal insufficiency requiring corticosteroid replacement therapy and may have an increased susceptibility to cancer. 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 (2): NP_005905, NP_877423* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001208	MCM_dom	Domain
IPR008047	MCM_4	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

Pfam: PF00493, PF14551, PF17207, PF17855, PF21128

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (100 total): strand 27, helix 23, modified residue 18, binding site 8, turn 8, region of interest 2, cross-link 2, sequence variant 2, sequence conflict 2, short sequence motif 2, initiator methionine 1, chain 1, site 1, domain 1, mutagenesis site 1, compositionally biased region 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-P33991-F1	74.25	0.14

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): 643 (arginine finger)

Ligand- & substrate-binding residues (8): 516; 517; 618; 643; 732; 735; 471; 497

Post-translational modifications (20): 2, 6, 7, 19, 26, 31, 32, 34, 102, 105, 110, 120, 131, 142, 145, 220, 450, 858, 439, 798

Mutagenesis-validated functional residues (1):

Position	Phenotype
364	reduced mcm complex dna helicase activity. no effect on mcm complex formation. no effect on mcm complex ssdna binding an

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: 435 (showing top): E2F_Q4, WU_APOPTOSIS_BY_CDKN1A_VIA_TP53, REACTOME_DNA_REPLICATION, E2F_Q4_01, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, KANG_DOXORUBICIN_RESISTANCE_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, E2F4DP1_01, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, PAL_PRMT5_TARGETS_UP, GOBP_CELL_CYCLE_DNA_REPLICATION, CROONQUIST_NRAS_SIGNALING_DN, MATTIOLI_MGUS_VS_PCL, GOBP_DNA_STRAND_ELONGATION_INVOLVED_IN_DNA_REPLICATION, REACTOME_ACTIVATION_OF_ATR_IN_RESPONSE_TO_REPLICATION_STRESS

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

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

GO Cellular Component (7): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), membrane (GO:0016020), MCM complex (GO:0042555), CMG complex (GO:0071162), chromosome (GO:0005694)

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
DNA metabolic process	2
DNA-templated DNA replication	2
ATP-dependent activity	2
cellular anatomical structure	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
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 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
protein-containing complex	1
MCM core complex	1
nuclear chromosome	1
GINS complex	1
DNA replication preinitiation complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

3295 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCM4	MCM5	P33992	991
MCM4	MCM3	P25205	991
MCM4	MCM7	P33993	991
MCM4	MCM6	Q14566	991
MCM4	MCM10	Q7L590	976
MCM4	CDC7	O00311	968
MCM4	DBF4	Q9UBU7	968
MCM4	CDC6	Q99741	954
MCM4	MCMBP	Q9BTE3	939
MCM4	CDT1	Q9H211	931
MCM4	TICRR	Q7Z2Z1	908
MCM4	CDC45	O75419	907
MCM4	PRKDC	P78527	839
MCM4	ORC5	O43913	833
MCM4	GINS4	Q9BRT9	831

IntAct

263 interactions, top by confidence:

A	B	Type	Score
MCM7	MCM4	psi-mi:“MI:0914”(association)	0.930
MCM4	MCM7	psi-mi:“MI:0915”(physical association)	0.930
MCM4	MCM7	psi-mi:“MI:0407”(direct interaction)	0.930
MCM4	MCM7	psi-mi:“MI:0914”(association)	0.930
MCM2	MCM3	psi-mi:“MI:0915”(physical association)	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
MCMBP	MCM4	psi-mi:“MI:0914”(association)	0.850
MCM5	MCM3	psi-mi:“MI:0914”(association)	0.850
MCM2	MCM4	psi-mi:“MI:0914”(association)	0.830
MCM6	MCM3	psi-mi:“MI:0914”(association)	0.810
MCM7	MCM3	psi-mi:“MI:0914”(association)	0.810
PLK1	SPAG9	psi-mi:“MI:0914”(association)	0.790
CDK19	MED19	psi-mi:“MI:0914”(association)	0.770
H2AX	PPM1G	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710

BioGRID (489): MCM4 (Affinity Capture-MS), MCM4 (Affinity Capture-RNA), MCM4 (Affinity Capture-RNA), MCM4 (Affinity Capture-MS), MCM4 (Affinity Capture-MS), MCM4 (Affinity Capture-MS), MCM4 (Affinity Capture-MS), MCM4 (Affinity Capture-MS), MCM4 (Affinity Capture-MS), MCM4 (Affinity Capture-MS), MCM4 (Reconstituted Complex), INPPL1 (Co-fractionation), KPNA4 (Co-fractionation), MAPRE2 (Co-fractionation), MCM3 (Co-fractionation)

ESM2 similar proteins: A5VPI9, A6U659, B2J573, B8AMB8, B8GXB5, F1LNJ2, O05560, O22437, O24133, P06974, P0AFF6, P0AFF7, P0AFF8, P0AFF9, P0CG26, P26418, P27580, P30333, P33991, P37430, P38035, P9WNA2, P9WNA3, Q02870, Q04955, Q110K2, Q1MIX8, Q2KA54, Q2YN11, Q31KM4, Q3M7Y0, Q51465, Q52880, Q57E90, Q5N192, Q5VZM2, Q5XK83, Q63487, Q6ATS0, Q6NTA4

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

11 interactions.

A	Effect	B	Mechanism
CDK1	“down-regulates activity”	MCM4	phosphorylation
CDK2	“down-regulates activity”	MCM4	phosphorylation
ATR	up-regulates	MCM4	phosphorylation
CDC7	up-regulates	MCM4	phosphorylation
CyclinA2/CDK2	down-regulates	MCM4	phosphorylation
MCM4	“form complex”	MCM	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 190 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	8	22.3×	2e-07
DNA Replication Pre-Initiation	8	21.7×	2e-07
Activation of ATR in response to replication stress	8	20.6×	2e-07
Synthesis of DNA	8	20.6×	2e-07
G1/S Transition	10	19.9×	2e-08
DNA Replication	9	18.3×	1e-07
Switching of origins to a post-replicative state	7	18.0×	3e-06
S Phase	11	17.0×	2e-08

GO biological processes:

GO term	Partners	Fold	FDR
regulation of DNA-templated DNA replication initiation	5	35.1×	5e-05
DNA replication initiation	8	33.3×	4e-08
heterochromatin formation	9	15.3×	2e-06
nucleosome assembly	16	15.0×	1e-11
DNA replication	8	8.8×	6e-04
protein import into nucleus	7	6.7×	8e-03
chromatin organization	10	6.6×	6e-04
DNA repair	10	4.3×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	379
Likely benign	275
Benign	20

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
37234	NM_182746.3(MCM4):c.71-2A>G	Pathogenic
930225	NM_182746.3(MCM4):c.220C>T (p.Gln74Ter)	Likely pathogenic

SpliceAI

1864 predictions. Top by Δscore:

Variant	Effect	Δscore
8:47961210:GACGC:G	donor_gain	1.0000
8:47961503:T:TA	acceptor_gain	1.0000
8:47961505:T:TA	acceptor_gain	1.0000
8:47961507:T:TA	acceptor_gain	1.0000
8:47961512:C:G	acceptor_gain	1.0000
8:47961513:A:AG	acceptor_gain	1.0000
8:47961514:A:G	acceptor_gain	1.0000
8:47961515:G:GG	acceptor_gain	1.0000
8:47961641:G:GT	donor_gain	1.0000
8:47961677:TCAGG:T	donor_loss	1.0000
8:47961678:CAGG:C	donor_loss	1.0000
8:47962051:A:AG	acceptor_gain	1.0000
8:47962052:G:GG	acceptor_gain	1.0000
8:47962298:T:TA	acceptor_gain	1.0000
8:47962300:T:TA	acceptor_gain	1.0000
8:47962300:TGTAG:T	acceptor_loss	1.0000
8:47962301:GTAGG:G	acceptor_loss	1.0000
8:47962303:A:AG	acceptor_gain	1.0000
8:47962303:AG:A	acceptor_gain	1.0000
8:47962304:G:GA	acceptor_gain	1.0000
8:47962304:G:T	acceptor_loss	1.0000
8:47962304:GG:G	acceptor_gain	1.0000
8:47962304:GGC:G	acceptor_gain	1.0000
8:47962304:GGCA:G	acceptor_gain	1.0000
8:47962405:AGGTG:A	donor_loss	1.0000
8:47962406:GGTG:G	donor_loss	1.0000
8:47962407:G:GG	donor_gain	1.0000
8:47962407:GT:G	donor_loss	1.0000
8:47962408:T:G	donor_loss	1.0000
8:47962756:A:AG	acceptor_gain	1.0000

AlphaMissense

5676 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:47970624:G:C	K516N	1.000
8:47970624:G:T	K516N	1.000
8:47970691:A:C	S539R	1.000
8:47970693:T:A	S539R	1.000
8:47970693:T:G	S539R	1.000
8:47970704:T:C	L543P	1.000
8:47970710:C:A	A545E	1.000
8:47970789:C:G	C571W	1.000
8:47971345:G:A	G602E	1.000
8:47971360:T:C	L607P	1.000
8:47971394:T:A	N618K	1.000
8:47971394:T:G	N618K	1.000
8:47971410:T:A	W624R	1.000
8:47971410:T:C	W624R	1.000
8:47971468:G:T	R643M	1.000
8:47966213:G:C	G287R	0.999
8:47966214:G:A	G287D	0.999
8:47966270:T:C	C306R	0.999
8:47967372:T:C	L354P	0.999
8:47967465:G:A	G385E	0.999
8:47970054:G:C	K477N	0.999
8:47970054:G:T	K477N	0.999
8:47970511:G:A	G479R	0.999
8:47970511:G:C	G479R	0.999
8:47970604:G:C	G510R	0.999
8:47970605:G:A	G510D	0.999
8:47970605:G:T	G510V	0.999
8:47970622:A:C	K516Q	0.999
8:47970622:A:G	K516E	0.999
8:47970623:A:T	K516M	0.999

dbSNP variants (sampled 300 via entrez): RS1000359033 (8:47970710 C>G,T), RS1000485269 (8:47967649 T>A), RS1000503466 (8:47971571 C>T), RS1000671381 (8:47961116 G>C), RS1000692546 (8:47972081 A>C), RS1000780765 (8:47967967 T>C,G), RS1000808219 (8:47972372 T>C), RS1001054659 (8:47966955 G>A), RS1001095395 (8:47976559 G>A,T), RS1001180546 (8:47961801 T>G), RS1001261937 (8:47971315 T>C,G), RS1001753428 (8:47972283 C>T), RS1001825418 (8:47966130 A>C,G), RS1001880510 (8:47961936 G>A,T), RS1001932658 (8:47972057 C>T)

Disease associations

OMIM: gene MIM:602638 | disease phenotypes: MIM:609981, MIM:615966

GenCC curated gene-disease

Disease	Classification	Inheritance
primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Moderate	AR

Mondo (3): primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency (MONDO:0012383), severe combined immunodeficiency due to DNA-PKcs deficiency (MONDO:0014423), microcephaly (MONDO:0001149)

Orphanet (2): Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency (Orphanet:75391), Severe combined immunodeficiency due to DNA-PKcs deficiency (Orphanet:317425)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000846	Adrenal insufficiency
HP:0000953	Hyperpigmentation of the skin
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001744	Splenomegaly
HP:0002093	Respiratory insufficiency
HP:0002205	Recurrent respiratory infections
HP:0002240	Hepatomegaly
HP:0002716	Lymphadenopathy
HP:0002878	Respiratory failure
HP:0004322	Short stature
HP:0004429	Recurrent viral infections
HP:0005523	Lymphoproliferative disorder
HP:0008897	Postnatal growth retardation
HP:0011342	Mild global developmental delay
HP:0011410	Caesarean section
HP:0011749	Adrenocorticotropic hormone excess
HP:0040012	Chromosome breakage
HP:0040218	Reduced total natural killer cell count

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST004601_107	Red blood cell count	2.000000e-10
GCST004602_69	Mean corpuscular volume	4.000000e-12
GCST90002379_119	Basophil count	1.000000e-10
GCST90002380_59	Basophil percentage of white cells	2.000000e-10
GCST90002382_173	Eosinophil percentage of white cells	2.000000e-11
GCST90002392_583	Mean corpuscular volume	4.000000e-18
GCST90002396_428	Mean reticulocyte volume	4.000000e-37
GCST90002397_339	Mean spheric corpuscular volume	1.000000e-22
GCST90002405_509	Reticulocyte count	3.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count
EFO:0005090	basophil count
EFO:0007992	basophil percentage of leukocytes
EFO:0007991	eosinophil percentage of leukocytes
EFO:0010701	mean reticulocyte volume
EFO:0007986	reticulocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C566492	Natural Killer Cell Deficiency, Familial Isolated (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105745 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,305 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL483158	ALISERTIB	3	2,305

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 5 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.12	Kd	76.29	nM	CHEMBL5653589
7.12	ED50	76.29	nM	CHEMBL5653589
6.20	Kd	629	nM	ALISERTIB

PubChem BioAssay actives

2 with measured affinity, of 239 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	2148732: Binding affinity to human MCM4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0763	uM
4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid	1425072: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.6290	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, affects expression	4
sodium arsenite	increases expression, affects binding, decreases reaction, decreases expression	4
Arsenic Trioxide	decreases expression, increases expression	4
Benzo(a)pyrene	decreases expression, increases expression	4
Cyclosporine	decreases expression	4
Cadmium Chloride	decreases expression	3
cobaltous chloride	decreases expression	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Copper	affects binding, decreases expression	2
Doxorubicin	affects expression, decreases expression	2
Oxygen	decreases expression	2
Quercetin	increases expression, decreases expression, affects cotreatment	2
Smoke	decreases expression, increases abundance	2
Tretinoin	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
afuresertib	decreases expression	1
FR900359	increases phosphorylation	1
TAK-243	decreases sumoylation	1
geldanamycin	increases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
trichostatin A	decreases expression	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
tetrabromobisphenol A	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991785	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.