MCM5

Summary

MCM5 (minichromosome maintenance complex component 5, HGNC:6948) is a protein-coding gene on chromosome 22q12.3, encoding DNA replication licensing factor MCM5 (P33992). 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 99.7% of cancer cell lines).

The protein encoded by this gene is structurally very similar to the CDC46 protein from S. cerevisiae, a protein involved in the initiation of DNA replication. The encoded protein is a member of the MCM family of chromatin-binding proteins and can interact with at least two other members of this family. The encoded protein is upregulated in the transition from the G0 to G1/S phase of the cell cycle and may actively participate in cell cycle regulation.

Source: NCBI Gene 4174 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Meier-Gorlin syndrome 8 (Limited, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 485 total — 1 pathogenic
• Phenotypes (HPO): 12
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_006739

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6948
Approved symbol	MCM5
Name	minichromosome maintenance complex component 5
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000100297
Ensembl biotype	protein_coding
OMIM	602696
Entrez	4174

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000216122, ENST00000382011, ENST00000416905, ENST00000417343, ENST00000444778, ENST00000451351, ENST00000464908, ENST00000465557, ENST00000493076, ENST00000493569, ENST00000909967, ENST00000909968, ENST00000917543, ENST00000917544, ENST00000917545, ENST00000917546, ENST00000917547, ENST00000917548, ENST00000917549, ENST00000917550, ENST00000917551

RefSeq mRNA: 1 — MANE Select: NM_006739 NM_006739

CCDS: CCDS13915

Canonical transcript exons

ENST00000216122 — 17 exons

Exon	Start	End
ENSE00000653523	35403414	35403542
ENSE00001800554	35403207	35403333
ENSE00001805573	35408408	35408563
ENSE00001873802	35400140	35400208
ENSE00001883977	35424154	35425431
ENSE00002704414	35400431	35400605
ENSE00003200140	35423214	35423341
ENSE00003206772	35421318	35421460
ENSE00003465175	35415829	35415972
ENSE00003527455	35419884	35420012
ENSE00003544760	35413875	35413986
ENSE00003550023	35416339	35416404
ENSE00003660683	35416638	35416814
ENSE00003666157	35417744	35417856
ENSE00003677198	35410744	35410910
ENSE00003680744	35412510	35412681
ENSE00003788046	35406553	35406725

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 95.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.4665 / max 445.3795, expressed in 1804 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191993	49.0094	1804
191996	0.2423	107
191994	0.1607	84
191995	0.0540	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	95.90	gold quality
ganglionic eminence	UBERON:0004023	95.12	gold quality
embryo	UBERON:0000922	95.05	gold quality
vermiform appendix	UBERON:0001154	94.79	gold quality
granulocyte	CL:0000094	93.24	gold quality
bone marrow cell	CL:0002092	93.02	gold quality
lymph node	UBERON:0000029	92.92	gold quality
spleen	UBERON:0002106	92.55	gold quality
leukocyte	CL:0000738	90.81	gold quality
monocyte	CL:0000576	90.70	gold quality
mononuclear cell	CL:0000842	90.55	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.38	gold quality
bone marrow	UBERON:0002371	90.30	gold quality
rectum	UBERON:0001052	90.28	gold quality
caecum	UBERON:0001153	90.20	gold quality
mucosa of transverse colon	UBERON:0004991	89.96	gold quality
left ovary	UBERON:0002119	89.76	gold quality
bone element	UBERON:0001474	88.87	gold quality
oocyte	CL:0000023	88.78	gold quality
blood	UBERON:0000178	88.70	gold quality
cervix squamous epithelium	UBERON:0006922	88.69	gold quality
right ovary	UBERON:0002118	88.64	gold quality
trabecular bone tissue	UBERON:0002483	88.57	gold quality
secondary oocyte	CL:0000655	88.55	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.24	gold quality
stromal cell of endometrium	CL:0002255	88.10	gold quality
esophagus mucosa	UBERON:0002469	87.81	gold quality
smooth muscle tissue	UBERON:0001135	86.82	gold quality
tongue squamous epithelium	UBERON:0006919	86.82	silver quality
tonsil	UBERON:0002372	86.70	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-7037	yes	325.78
E-ENAD-20	yes	307.67
E-GEOD-93593	yes	236.46
E-MTAB-10662	yes	194.36
E-MTAB-7052	yes	147.13
E-CURD-114	yes	128.67
E-CURD-122	yes	22.50
E-ANND-3	yes	8.73
E-MTAB-6911	no	535.75
E-MTAB-6108	no	76.95

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
STAT1	Unknown

Upstream regulators (CollecTRI, top): CREB1, E2F1, E2F2, E2F3, E2F4, FOXO1, MYCN, TP53

miRNA regulators (miRDB)

8 targeting MCM5, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-132-5P	96.61	65.79	115
HSA-MIR-4649-5P	93.02	63.85	141
HSA-MIR-6729-5P	93.02	62.76	138

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Results further confirm the importance of MCM5 in malignant transformation and in the pathogenesis of cervical dysplasia. (PMID:15696126)
• The DNA replication factor MCM5 is essential for Stat1-mediated transcriptional activation. (PMID:16199513)
• MCM5 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)
• results demonstrate pattern and frequency of MCM5 expression in various skin diseases (PMID:17988337)
• Immunofluorescence technology to quantify cervical cell expression of two biomarkers p16(INK4A) and Mcm5 was developed and evaluated by both microscopy and flow cytometry. (PMID:18181189)
• No significant association was observed between MCM-5 protein expression and the clinicopathological characteristics of colon cancer examined. (PMID:18465232)
• Cyclin E is shown to directly interact with and colocalize on centrosomes with the DNA replication factor MCM5 in a centrosomal localization sequence-dependent but Cdk2-independent manner. (PMID:18799789)
• Analysis of MCM5 expression in aggressive fibromatosis (desmoid tumor) is reported. (PMID:19130399)
• 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)
• MCM-5 expression was significantly associated with tumor size, presence of lymph node metastases and tumor histopathological stage. Patients with high MCM-5 expression had significantly shorter survival times. (PMID:20694513)
• Could use the urinary hTERT, SENP1, PPP1CA, and MCM5 mRNA to detect bladder cancer recurrence. (PMID:21106093)
• MicroRNA miR-885-5p targets CDK2 and MCM5, activates p53 and inhibits proliferation and survival. (PMID:21233845)
• lack of MCM5 proteins expression which may explain commonly known low mitotic activity of desmoid tumour cells (PMID:21478101)
• 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)
• The results of this study demonistrated that Mcm5 shows a highly significant correlation with Alcohol use disorders-induced decreases in the volume of the left parietal supramarginal gyrus and neuropsychological measures. (PMID:23095216)
• Data indicate that MCM-BP binds USP7 on chromatin and can mediate an interaction between the USP7 and MCM proteins. (PMID:24190967)
• The increased expression of MCM5 protein begins at the oral pre-cancerous stage and is significantly associated with the aggressive progression and poor prognosis of OSCC. (PMID:24245508)
• we could consider miRNA-10b and MCM5 mRNA as prognostic markers and potential therapeutic targets in breast cancer to be applied to other patient data sets. (PMID:25596707)
• Our findings support the hypothesis that MCM5 targeting may be regarded as an effective molecular therapy against anaplastic thyroid carcinoma (PMID:26911376)
• The RAS-related nuclear protein ((P) ran), breast cancer metastasis suppressor 1 ((P) brms1) and minichromosome maintenance complex component 5 ((P) mcm5) promoters have the specificity and strength needed for cancer-specific expression-targeted gene therapy. (PMID:27140445)
• 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)
• the incorporation of physiological levels of MCM5 into HIV-1 virions facilitates viral cDNA accumulation in newly infected cells, probably by modifying nucleic acid configuration during reverse transcription. (PMID:27414250)
• MCM5 is a novel gene involved in Meier-Gorlin syndrome. (PMID:28198391)
• MCM5 expression is associated with the malignant status and poor prognosis in cervical adenocarcinoma patients. (PMID:29253764)
• Minichromosome maintenance 5 was shown as an independent prognostic biomarker for patients with cervical cancer (PMID:29642758)
• Study results suggest that MCM5 is a trustable cell proliferation marker with higher sensitivity compared with Ki-67 and may be useful to predict the biological behavior of conventional ameloblastoma and unicystic ameloblastoma. (PMID:29845895)
• 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)
• Positive correlations were demonstrated between the expression levels of MCM5 and the Ki-67 antigen. In vitro studies have confirmed that the expression of MCM5 is elevated in cancer cells. MCM5 protein may be used as a potential marker of cancer cell proliferation in laryngeal squamous cell cancer . (PMID:31092424)
• 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)
• miR-3607, a biomarker of hepatocellular carcinoma invasion and aggressiveness: Its relationship with epithelial-mesenchymal transition process. (PMID:32311821)
• MCM5 urine expression (ADXBLADDER) is a reliable biomarker of high-risk non- muscle-invasive bladder cancer recurrence: A prospective matched case-control study. (PMID:32924986)
• Detection of MCM5 as a novel non-invasive aid for the diagnosis of endometrial and ovarian tumours. (PMID:33059604)
• LncRNA CARMN overexpression promotes prognosis and chemosensitivity of triple negative breast cancer via acting as miR143-3p host gene and inhibiting DNA replication. (PMID:34162418)
• CRNDE enhances the expression of MCM5 and proliferation in acute myeloid leukemia KG-1a cells by sponging miR-136-5p. (PMID:34408205)
• The Immunohistochemical Expression of MCM-3, -5, and -7 Proteins in the Uterine Fibroids. (PMID:34449552)
• The High Expression of Minichromosome Maintenance Complex Component 5 Is an Adverse Prognostic Factor in Lung Adenocarcinoma. (PMID:35360518)
• Diagnostic performance of minichromosome maintenance 5 (MCM5) in bladder cancer: A systematic review and meta-analysis. (PMID:35414492)
• Targeted inhibition of the expression of both MCM5 and MCM7 by miRNA-214 impedes DNA replication and tumorigenesis in hepatocellular carcinoma cells. (PMID:35490917)
• Phase separation of DDX21 promotes colorectal cancer metastasis via MCM5-dependent EMT pathway. (PMID:37029300)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mcm5	ENSDARG00000019507
mus_musculus	Mcm5	ENSMUSG00000005410
rattus_norvegicus	Mcm5	ENSRNOG00000014336
drosophila_melanogaster	Mcm5	FBGN0017577
caenorhabditis_elegans		WBGENE00003157

Paralogs (8): MCM2 (ENSG00000073111), MCM6 (ENSG00000076003), MCM4 (ENSG00000104738), MCM9 (ENSG00000111877), MCM3 (ENSG00000112118), MCM8 (ENSG00000125885), MCM7 (ENSG00000166508), MCMDC2 (ENSG00000178460)

Protein

Protein identifiers

DNA replication licensing factor MCM5 — P33992 (reviewed: P33992)

Alternative names: CDC46 homolog, P1-CDC46

All UniProt accessions (6): P33992, B1AHA9, B1AHB0, B1AHB1, B1AHB2, F8WFD7

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 ANKRD17. Interacts with MCMBP. Interacts with TONSL; the interaction is direct.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. UFMylated at Lys-583; UFMylation occurs at the ongoing replication fork and promotes the CMG replicative DNA helicase complex formation.

Disease relevance. Meier-Gorlin syndrome 8 (MGORS8) [MIM:617564] A form of Meier-Gorlin syndrome, a syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal. MGORS8 inheritance is autosomal recessive. 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. The MCM2-7 hexamer is the proposed physiological active complex.

Similarity. Belongs to the MCM family.

RefSeq proteins (1): NP_006730* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001208	MCM_dom	Domain
IPR008048	MCM5	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
IPR054125	MCM5_C	Domain

Pfam: PF00493, PF14551, PF17207, PF17855, PF21933

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (81 total): strand 28, helix 23, modified residue 6, turn 6, sequence conflict 5, sequence variant 4, short sequence motif 2, initiator methionine 1, chain 1, cross-link 1, mutagenesis site 1, domain 1, binding site 1, site 1

Structure

Experimental structures (PDB)

27 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
6XTY	ELECTRON MICROSCOPY	6.77

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P33992-F1	78.57	0.10

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): 513 (arginine finger)

Ligand- & substrate-binding residues (1): 371

Post-translational modifications (7): 396, 605, 696, 583, 2, 315, 392

Mutagenesis-validated functional residues (1):

Position	Phenotype
583	destabilizes the helicase complex, delaying origin firing and slowing replication fork progression.

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: 427 (showing top): MORF_DNMT1, REACTOME_DNA_REPLICATION, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, FISCHER_G1_S_CELL_CYCLE, MATTIOLI_MGUS_VS_PCL, REACTOME_ACTIVATION_OF_ATR_IN_RESPONSE_TO_REPLICATION_STRESS, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, FRASOR_RESPONSE_TO_SERM_OR_FULVESTRANT_DN, MITSIADES_RESPONSE_TO_APLIDIN_DN, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_1, MODULE_16, GNF2_MCM5, GNF2_RRM1, SHEPARD_BMYB_MORPHOLINO_DN, GOLDRATH_ANTIGEN_RESPONSE

GO Biological Process (5): double-strand break repair via break-induced replication (GO:0000727), DNA replication (GO:0006260), DNA replication initiation (GO:0006270), regulation of DNA-templated DNA replication initiation (GO:0030174), cell division (GO:0051301)

GO Molecular Function (12): DNA helicase activity (GO:0003678), DNA replication origin binding (GO:0003688), 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), 3’-5’ DNA helicase activity (GO:0043138)

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-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
DNA metabolic process	2
ATP-dependent activity	2
DNA helicase activity	2
cellular anatomical structure	2
double-strand break repair via homologous recombination	1
DNA biosynthetic process	1
DNA-templated DNA replication	1
DNA replication initiation	1
regulation of DNA-templated DNA replication	1
cellular process	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
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
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

3406 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCM5	MCM3	P25205	991
MCM5	MCM4	P33991	991
MCM5	MCM7	P33993	991
MCM5	MCM6	Q14566	991
MCM5	CDC45	O75419	976
MCM5	MCM10	Q7L590	925
MCM5	CDC6	Q99741	923
MCM5	CDT1	Q9H211	917
MCM5	CDC7	O00311	904
MCM5	HMGXB4	Q9UGU5	862
MCM5	TOM1	O60784	844
MCM5	GINS1	Q14691	834
MCM5	ORC4	O43929	831
MCM5	ORC5	O43913	829
MCM5	CCNA2	P20248	818

IntAct

188 interactions, top by confidence:

A	B	Type	Score
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	MCM5	psi-mi:“MI:0915”(physical association)	0.890
MCMBP	MCM5	psi-mi:“MI:0914”(association)	0.890
MCM5	MCMBP	psi-mi:“MI:0915”(physical association)	0.890
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
MCMBP	MCM4	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

BioGRID (627): RBPMS (Two-hybrid), KRTAP10-7 (Two-hybrid), MCM5 (Affinity Capture-MS), MCM5 (Affinity Capture-MS), MCM5 (Affinity Capture-MS), MCM5 (Affinity Capture-MS), MCM5 (Affinity Capture-Western), MCM5 (Affinity Capture-Western), ILF2 (Affinity Capture-Western), RAD50 (Affinity Capture-Western), ILF3 (Affinity Capture-Western), MCM5 (Affinity Capture-Western), MCM5 (Affinity Capture-MS), MCM5 (Affinity Capture-MS), MCM5 (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

1 interactions.

A	Effect	B	Mechanism
MCM5	“form complex”	MCM	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 181 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	9	25.8×	1e-08
Activation of ATR in response to replication stress	9	23.7×	2e-08
DNA Replication Pre-Initiation	7	19.5×	5e-06
Synthesis of DNA	7	18.4×	7e-06
Orc1 removal from chromatin	11	17.2×	1e-08
Switching of origins to a post-replicative state	6	15.8×	1e-04
DNA Replication	7	14.6×	3e-05
Mitotic G1 phase and G1/S transition	9	14.5×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
regulation of DNA-templated DNA replication initiation	5	33.3×	1e-04
DNA replication initiation	8	31.6×	1e-07
DNA replication	11	11.5×	1e-06
DNA damage response	12	4.1×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	282
Likely benign	160
Benign	23

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
430637	NM_006739.4(MCM5):c.1397C>T (p.Thr466Ile)	Pathogenic

SpliceAI

2227 predictions. Top by Δscore:

Variant	Effect	Δscore
22:35400206:GAG:G	donor_gain	1.0000
22:35400207:AGGTG:A	donor_loss	1.0000
22:35400209:G:GA	donor_loss	1.0000
22:35400605:GGTG:G	donor_loss	1.0000
22:35403170:A:AG	acceptor_gain	1.0000
22:35403171:C:G	acceptor_gain	1.0000
22:35403192:ATGT:A	acceptor_gain	1.0000
22:35403193:T:G	acceptor_gain	1.0000
22:35403193:T:TA	acceptor_gain	1.0000
22:35403195:T:TA	acceptor_gain	1.0000
22:35403201:C:G	acceptor_gain	1.0000
22:35403202:TCCA:T	acceptor_loss	1.0000
22:35403203:CCA:C	acceptor_loss	1.0000
22:35403204:CAGG:C	acceptor_loss	1.0000
22:35403205:A:AG	acceptor_gain	1.0000
22:35403205:AG:A	acceptor_gain	1.0000
22:35403205:AGG:A	acceptor_gain	1.0000
22:35403205:AGGG:A	acceptor_loss	1.0000
22:35403206:G:A	acceptor_loss	1.0000
22:35403206:G:GG	acceptor_gain	1.0000
22:35403206:GG:G	acceptor_gain	1.0000
22:35403206:GGG:G	acceptor_gain	1.0000
22:35403206:GGGA:G	acceptor_gain	1.0000
22:35403206:GGGAT:G	acceptor_gain	1.0000
22:35403330:GCTG:G	donor_gain	1.0000
22:35403331:CTG:C	donor_gain	1.0000
22:35403331:CTGGT:C	donor_loss	1.0000
22:35403332:TGG:T	donor_loss	1.0000
22:35403334:G:GG	donor_gain	1.0000
22:35403334:GTGA:G	donor_loss	1.0000

AlphaMissense

4844 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:35400551:T:C	F38S	1.000
22:35403215:T:C	L59P	1.000
22:35406586:G:C	G153R	1.000
22:35406587:G:A	G153D	1.000
22:35406643:T:A	C172S	1.000
22:35406643:T:C	C172R	1.000
22:35406644:G:C	C172S	1.000
22:35406645:C:G	C172W	1.000
22:35406718:T:A	C197S	1.000
22:35406718:T:C	C197R	1.000
22:35406719:G:C	C197S	1.000
22:35408430:T:C	C207R	1.000
22:35408466:T:C	C219R	1.000
22:35408497:T:C	L229P	1.000
22:35410770:G:A	G260E	1.000
22:35410790:G:C	G267R	1.000
22:35413916:T:C	L378P	1.000
22:35413924:G:A	G381R	1.000
22:35413924:G:C	G381R	1.000
22:35413924:G:T	G381W	1.000
22:35413925:G:A	G381E	1.000
22:35413925:G:T	G381V	1.000
22:35413933:G:T	G384W	1.000
22:35413942:A:C	K387Q	1.000
22:35413944:G:C	K387N	1.000
22:35413944:G:T	K387N	1.000
22:35413946:C:T	S388F	1.000
22:35413955:T:C	L391P	1.000
22:35415841:G:A	G406R	1.000
22:35415841:G:C	G406R	1.000

dbSNP variants (sampled 300 via entrez): RS1000007096 (22:35414504 A>G), RS1000048780 (22:35433409 G>C), RS1000153612 (22:35442543 G>A), RS1000213765 (22:35399296 G>A,C), RS1000260061 (22:35407788 A>G), RS1000294083 (22:35418360 T>C), RS1000370315 (22:35404173 A>G), RS1000386821 (22:35451455 C>G,T), RS1000422794 (22:35404049 A>C), RS1000510830 (22:35429044 A>G), RS1000651527 (22:35424686 T>C), RS1000717779 (22:35430715 C>G,T), RS1000720028 (22:35434028 A>G), RS1000771634 (22:35440971 C>T), RS1000804065 (22:35408062 G>C)

Disease associations

OMIM: gene MIM:602696 | disease phenotypes: MIM:617564, MIM:103050

GenCC curated gene-disease

Disease	Classification	Inheritance
Meier-Gorlin syndrome 8	Limited	Unknown

Mondo (2): Meier-Gorlin syndrome 8 (MONDO:0033046), adenylosuccinate lyase deficiency (MONDO:0007068)

Orphanet (1): Adenylosuccinate lyase deficiency (Orphanet:46)

HPO phenotypes

12 total (12 of 12 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000160	Narrow mouth
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0001511	Intrauterine growth retardation
HP:0003593	Infantile onset
HP:0004325	Decreased body weight
HP:0008551	Microtia
HP:0008689	Bilateral cryptorchidism
HP:0011126	Nephroptosis
HP:0012471	Thick vermilion border
HP:0012583	Unilateral renal hypoplasia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005958_13	Waist-to-hip ratio adjusted for BMI (age >50)	1.000000e-06
GCST005962_33	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	6.000000e-06
GCST007576_283	Chronotype	1.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0008328	chronotype measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538235	Adenylosuccinate lyase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630815 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.19	Kd	6508	nM	CHEMBL3752910
5.19	ED50	6508	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 13 total; 1 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-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148733: Binding affinity to human MCM5 incubated for 45 mins by Kinobead based pull down assay	kd	6.5082	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects expression, decreases expression	6
sodium arsenite	affects methylation, affects cotreatment, decreases expression, increases expression	6
(+)-JQ1 compound	decreases expression	3
Air Pollutants	increases abundance, increases oxidation, affects expression, increases expression, affects cotreatment	3
Benzo(a)pyrene	decreases expression, increases expression, increases methylation	3
Estradiol	decreases reaction, increases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, affects expression, decreases expression	3
Cyclosporine	decreases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
trichostatin A	affects expression, decreases expression	2
cobaltous chloride	decreases expression	2
Arsenic Trioxide	decreases expression, increases expression	2
Cadmium	increases abundance, increases expression, decreases expression	2
Copper	decreases expression, affects binding	2
Doxorubicin	decreases expression	2
Oxygen	decreases expression	2
Ozone	increases abundance, affects expression, affects cotreatment, increases oxidation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	increases expression, decreases expression, increases abundance	2
Tretinoin	affects cotreatment, decreases expression	2
tert-Butylhydroperoxide	affects expression, decreases expression	2
Vitamin K 3	affects expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
propionaldehyde	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects response to substance, affects expression	1
methylselenic acid	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	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
CHEMBL4605096	Binding	Induction of ubiquitination of MCM5 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)

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

Trial	Phase	Status	Title
NCT03776656	PHASE2	COMPLETED	Evaluation of a Treatment With Allopurinol in Adenylosuccinate Lyase Deficiency