MCM8

Summary

MCM8 (minichromosome maintenance 8 homologous recombination repair factor, HGNC:16147) is a protein-coding gene on chromosome 20p12.3, encoding DNA helicase MCM8 (Q9UJA3). Component of the MCM8-MCM9 complex, which is involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR).

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 the mini-chromosome maintenance proteins is a key component of the pre-replication complex and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein contains the central domain that is conserved among the mini-chromosome maintenance proteins. The encoded protein may interact with other mini-chromosome maintenance proteins and play a role in DNA replication. This gene may be associated with length of reproductive lifespan and menopause. Alternatively spliced transcript variants encoding distinct isoforms have been described.

Source: NCBI Gene 84515 — RefSeq curated summary.

At a glance

• Gene–disease (curated): premature ovarian failure 10 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 173 total — 9 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 9
• MANE Select transcript: NM_032485

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16147
Approved symbol	MCM8
Name	minichromosome maintenance 8 homologous recombination repair factor
Location	20p12.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC4816, MGC12866, MGC119522, MGC119523, dJ967N21.5, REC
Ensembl gene	ENSG00000125885
Ensembl biotype	protein_coding
OMIM	608187
Entrez	84515

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000265187, ENST00000378883, ENST00000378886, ENST00000378896, ENST00000610722, ENST00000931170, ENST00000931171

RefSeq mRNA: 5 — MANE Select: NM_032485 NM_001281520, NM_001281521, NM_001281522, NM_032485, NM_182802

CCDS: CCDS13094, CCDS13095, CCDS63226, CCDS63227

Canonical transcript exons

ENST00000610722 — 19 exons

Exon	Start	End
ENSE00000562368	5963274	5963359
ENSE00000658277	5957126	5957229
ENSE00000658288	5958528	5958726
ENSE00000658290	5967436	5967587
ENSE00000658296	5982970	5983165
ENSE00000658298	5984781	5985000
ENSE00000658300	5985922	5986131
ENSE00000658302	5987282	5987358
ENSE00000658304	5993506	5993695
ENSE00000858954	5952011	5952163
ENSE00000858955	5967830	5968025
ENSE00000858956	5973056	5973196
ENSE00000858958	5977876	5978017
ENSE00000906725	5952424	5952528
ENSE00000906726	5954608	5954690
ENSE00000906727	5955102	5955251
ENSE00000990087	5994299	5998977
ENSE00001026568	5972007	5972037
ENSE00001424387	5950652	5951023

Expression profiles

Bgee: expression breadth ubiquitous, 226 present calls, max score 91.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.9458 / max 66.4794, expressed in 1403 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183384	4.2656	1283
183385	1.2208	639
183386	0.4593	215

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.00	gold quality
buccal mucosa cell	CL:0002336	85.48	gold quality
oocyte	CL:0000023	83.98	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.86	gold quality
secondary oocyte	CL:0000655	83.22	gold quality
trabecular bone tissue	UBERON:0002483	83.14	gold quality
biceps brachii	UBERON:0001507	81.47	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	81.20	gold quality
ventricular zone	UBERON:0003053	80.99	gold quality
bone element	UBERON:0001474	79.29	gold quality
bone marrow cell	CL:0002092	79.21	gold quality
bone marrow	UBERON:0002371	79.20	gold quality
deltoid	UBERON:0001476	78.91	silver quality
gastrocnemius	UBERON:0001388	78.62	gold quality
ganglionic eminence	UBERON:0004023	78.61	gold quality
right testis	UBERON:0004534	78.42	gold quality
muscle of leg	UBERON:0001383	78.02	gold quality
testis	UBERON:0000473	78.01	gold quality
skeletal muscle organ	UBERON:0014892	77.87	gold quality
left testis	UBERON:0004533	77.61	gold quality
skeletal muscle tissue	UBERON:0001134	77.54	gold quality
stromal cell of endometrium	CL:0002255	76.72	gold quality
tibialis anterior	UBERON:0001385	76.23	silver quality
vastus lateralis	UBERON:0001379	76.22	silver quality
quadriceps femoris	UBERON:0001377	76.10	silver quality
hindlimb stylopod muscle	UBERON:0004252	75.80	gold quality
heart right ventricle	UBERON:0002080	75.24	gold quality
bronchial epithelial cell	CL:0002328	75.12	gold quality
calcaneal tendon	UBERON:0003701	74.96	gold quality
muscle tissue	UBERON:0002385	74.91	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.90

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F2, E2F3, E2F4, MYCN, NFYA

miRNA regulators (miRDB)

48 targeting MCM8, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-892A	99.54	68.16	1141
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-122B-5P	99.46	70.81	1457

Literature-anchored findings (GeneRIF, showing 34)

• The MCM8 gene is located contrapodal to GCD10 at chromosome band 20p12.3-13. (PMID:12771218)
• MCM8 is a crucial component of the pre-RC and that the interaction between hMCM8 and hcdc6 is required for pre-RC assembly. (PMID:15684404)
• We find that MCM8, like MCM7, colocalizes on a specific DNA segment of the c-MYC replication initiation zone (c-MYC replicator) of DNA replications together with Cdc6 and cdk2, but differs with MCM7 in spatial relation to RPA70 during S phase. (PMID:18072282)
• Single nucleotide polymorphism in MCM8 is associated with menopause and the length of reproductive lifespan. (PMID:22131368)
• Single Nucleotide Polymorphism in MCM8 is associated with ovarian follicle number and menopause. (PMID:22696150)
• Chromatin immunoprecipitation analysis using human DR-GFP cells demonstrated that MCM8 and MCM9 proteins are rapidly recruited to DNA damage sites and promote RAD51 recruitment. (PMID:23401855)
• An autosomal recessive ovarian failure disorder caused by an MCM8 mutation that manifests with endocrine dysfunction and genomic instability. (PMID:25437880)
• MCM8, a component of the pre-replication complex, is crucial for gonadal development and maintenance in humans-both males and females. These (PMID:25873734)
• Suggest role for MCM8 in the pathogenesis of chronic myelogenous leukemia. (PMID:26823731)
• Novel mutations p. H317L and p. H601R in the MCM8 gene are potentially causative for primary ovarian insufficiency by dysfunctional DNA repair. (PMID:27573988)
• Significant number of potentially damaging and novel variants in MCM8 in primary ovarian insufficiency; multiallelic association with variants in DDR and MCM8-MCM9 interactome genes. (PMID:27802094)
• study showed that copy number increase and overexpression of MCM8 may play critical roles in human cancer development. (PMID:28481876)
• stalled replication forks can be restarted in S phase via homologous recombination using MCM8-9 as an alternative replicative helicase. (PMID:28487407)
• Additional support to the view that MCM8 mutations are involved in the primary ovarian insufficiency phenotype. (PMID:28863940)
• Conceptual MCM8-9 inhibitors will be powerful cancer-specific chemosensitizers for platinum compounds. (PMID:30648820)
• 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)
• Novel loss-of-function mutation in MCM8 causes premature ovarian insufficiency. (PMID:32048466)
• A Novel Phenotype Combining Primary Ovarian Insufficiency Growth Retardation and Pilomatricomas With MCM8 Mutation. (PMID:32242235)
• Crystal structure of the winged-helix domain of MCM8. (PMID:32295713)
• MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage. (PMID:32528060)
• Two novel mutations in the MCM8 gene shared by two Chinese siblings with primary ovarian insufficiency and short stature. (PMID:32652893)
• Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome. (PMID:32841224)
• Identification of mini-chromosome maintenance 8 as a potential prognostic marker and its effects on proliferation and apoptosis in gastric cancer. (PMID:33155430)
• Knockdown of MCM8 functions as a strategy to inhibit the development and progression of osteosarcoma through regulating CTGF. (PMID:33828075)
• Structural study of the N-terminal domain of human MCM8/9 complex. (PMID:34043945)
• MCM8 is regulated by EGFR signaling and promotes the growth of glioma stem cells through its interaction with DNA-replication-initiating factors. (PMID:34131285)
• Associations of MCM8 rs3761873 and rs16991617 variants with abnormal uterine bleeding induced by copper intrauterine device. (PMID:34889489)
• Activity, substrate preference and structure of the HsMCM8/9 helicase. (PMID:37309874)
• Enhancer-driven transcription of MCM8 by E2F4 promotes ATR pathway activation and glioma stem cell characteristics. (PMID:37349788)
• A novel cancer-germline gene DAZL promotes progression and cisplatin resistance of non-small cell lung cancer by upregulating JAK2 and MCM8. (PMID:38588931)
• Mechanism of DNA unwinding by MCM8-9 in complex with HROB. (PMID:38678026)
• MCM8 promotes gastric cancer progression through RPS15A and predicts poor prognosis. (PMID:38988047)
• MCM8 promotes lung cancer progression through upregulating DNAJC10. (PMID:39031896)
• Understanding the novel MCM8 gene mutation: primary ovarian insufficiency and uterine hypoplasia in siblings. (PMID:39074937)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mcm8	ENSDARG00000074326
mus_musculus	Mcm8	ENSMUSG00000027353
rattus_norvegicus	Mcm8	ENSRNOG00000021272
drosophila_melanogaster	rec	FBGN0003227

Paralogs (8): MCM2 (ENSG00000073111), MCM6 (ENSG00000076003), MCM5 (ENSG00000100297), MCM4 (ENSG00000104738), MCM9 (ENSG00000111877), MCM3 (ENSG00000112118), MCM7 (ENSG00000166508), MCMDC2 (ENSG00000178460)

Protein

Protein identifiers

DNA helicase MCM8 — Q9UJA3 (reviewed: Q9UJA3)

Alternative names: DNA 3’-5’ helicase MCM8, Minichromosome maintenance 8

All UniProt accessions (1): Q9UJA3

UniProt curated annotations — full annotation on UniProt →

Function. Component of the MCM8-MCM9 complex, which is involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR). The MCM8-MCM9 complex is a 3’-5’ DNA helicase and single-stranded (ss)DNA-stimulated ATPase which binds ssDNA in the presence of nucleoside triphosphates. Required for DNA resection by the MRE11-RAD50-NBN/NBS1 (MRN) complex by recruiting the MRN complex to the repair site and by promoting the complex nuclease activity. Indirectly regulates the recruitment of downstream effector RAD51 to DNA damage sites including DBSs and ICLs, probably by regulating the localization of the MNR complex. The MCM8-MCM9 complex is dispensable for DNA replication and S phase progression. May play a non-essential for DNA replication: may be involved in the activation of the prereplicative complex (pre-RC) during G(1) phase by recruiting CDC6 to the origin recognition complex (ORC). Facilitates somatic mitochondrial (mt)DNA recombination. Plays a key role during gametogenesis, probably by regulating HR. Stabilizes MCM9 protein.

Subunit / interactions. Component of the MCM8-MCM9 complex, which forms a heterohexamer with a repeating heterodimer of trimers configuration. Interacts with the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1. Interacts with RAD51; the interaction recruits RAD51 to DNA damage sites. Interacts with the MRN complex composed of MRE11, RAD50 and NBN/NBS1. Interacts with CDC6 and ORC2. Interacts with HROB; the interaction recruits the MCM8-MCM9 complex to DNA damage sites and stimulates the helicase activity.

Subcellular location. Nucleus. Chromosome. Cytoplasm. Mitochondrion matrix.

Tissue specificity. Highest levels in placenta, lung and pancreas. Low levels in skeletal muscle and kidney. Expressed in various tumors with highest levels in colon and lung cancers.

Disease relevance. Premature ovarian failure 10 (POF10) [MIM:612885] An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The helicase reaction is stimulated by the C-terminal domain of HROB; binding of HROB changes the conformation of the complex.

Cofactor. Binds 1 Zn(2+) ion per subunit; may also bind Fe(3+) at the same site.

Domain organisation. The ADP-bound heterohexamer forms around a central hole large enough to bind double-stranded (ds)DNA. Has 2 tiers; the N-terminal tier (residues 1-365) and the C-terminal ATPase tier (residues 401-754) joined by a linker which is essential for function. The C-terminal tier rotates compared to the N-terminal tier, which is required for helicase activity. ATP binds in the C-terminal AAA(+) ATPase domain at the boundary between the alternating subunits.

Induction. By E2F1.

Miscellaneous. No experimental confirmation available. According to PubMed:12771218, this isoform could be derived from an aberrant mRNA form found in placental choriocarcinoma.

Similarity. Belongs to the MCM family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9UJA3-1	1	yes
Q9UJA3-2	2
Q9UJA3-3	3
Q9UJA3-4	4

RefSeq proteins (5): NP_001268449, NP_001268450, NP_001268451, NP_115874, NP_877954 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001208	MCM_dom	Domain
IPR003593	AAA+_ATPase	Domain
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR031327	MCM	Family
IPR033762	MCM_OB	Domain
IPR041562	MCM_lid	Domain
IPR056875	MCM8/REC_WHD	Domain
IPR058767	MCM8_N	Domain

Pfam: PF00493, PF17207, PF17855, PF25051, PF26065

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (65 total): strand 17, helix 13, binding site 7, sequence variant 7, mutagenesis site 4, splice variant 3, turn 3, region of interest 2, sequence conflict 2, short sequence motif 2, chain 1, domain 1, site 1, modified residue 1, compositionally biased region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6L0O	X-RAY DIFFRACTION	1.21
7DP3	X-RAY DIFFRACTION	2.55
8S94	ELECTRON MICROSCOPY	3.94
7YOX	ELECTRON MICROSCOPY	3.95
8S92	ELECTRON MICROSCOPY	4.06
8S91	ELECTRON MICROSCOPY	4.3
7WI7	X-RAY DIFFRACTION	6.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UJA3-F1	75.55	0.20

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): 586 (arginine finger)

Ligand- & substrate-binding residues (7): 269; 457; 459; 482; 242; 245; 264

Post-translational modifications (1): 630

Mutagenesis-validated functional residues (4):

Position	Phenotype
295	no change in mcm8-mcm9 helicase activity.
345–350	decreased mcm8-mcm9 helicase activity.
369–377	linker reduction, loss of mcm8-mcm9 helicase activity.
456	decreases the formation of mre11 and rpa1 foci in response to cisplatin-induced dna damage.

Function

Pathways and Gene Ontology

Reactome pathways

20 pathways

ID	Pathway
R-HSA-113507	E2F-enabled inhibition of pre-replication complex formation
R-HSA-176187	Activation of ATR in response to replication stress
R-HSA-176974	Unwinding of DNA
R-HSA-68689	CDC6 association with the ORC:origin complex
R-HSA-68949	Orc1 removal from chromatin
R-HSA-68962	Activation of the pre-replicative complex
R-HSA-113510	E2F mediated regulation of DNA replication
R-HSA-1640170	Cell Cycle
R-HSA-453279	Mitotic G1 phase and G1/S transition
R-HSA-68867	Assembly of the pre-replicative complex
R-HSA-69002	DNA Replication Pre-Initiation
R-HSA-69052	Switching of origins to a post-replicative state
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: 218 (showing top): GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, E2F_Q4, REACTOME_DNA_REPLICATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, E2F4DP1_01, REACTOME_ACTIVATION_OF_ATR_IN_RESPONSE_TO_REPLICATION_STRESS, GOBP_MALE_GAMETE_GENERATION, USF_C, WEI_MYCN_TARGETS_WITH_E_BOX, E2F1DP1_01, E2F_Q3, E2F1DP2_01, GOBP_PROTEIN_LOCALIZATION_TO_CHROMATIN, GOBP_PROTEIN_STABILIZATION

GO Biological Process (9): double-strand break repair via homologous recombination (GO:0000724), DNA damage response (GO:0006974), female gamete generation (GO:0007292), recombinational interstrand cross-link repair (GO:0036298), male gamete generation (GO:0048232), protein stabilization (GO:0050821), mismatch repair involved in maintenance of fidelity involved in DNA-dependent DNA replication (GO:0070716), protein localization to chromatin (GO:0071168), DNA repair (GO:0006281)

GO Molecular Function (15): chromatin binding (GO:0003682), single-stranded DNA binding (GO:0003697), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), enzyme binding (GO:0019899), MutLbeta complex binding (GO:0032406), MutSalpha complex binding (GO:0032407), MutSbeta complex binding (GO:0032408), 3’-5’ DNA helicase activity (GO:0043138), 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 (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), MCM complex (GO:0042555), MCM8-MCM9 complex (GO:0097362)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
DNA Replication Pre-Initiation	2
G1/S Transition	2
Cell Cycle, Mitotic	2
DNA Replication	2
Synthesis of DNA	2
Cell Cycle	2
E2F mediated regulation of DNA replication	1
G2/M Checkpoints	1
DNA strand elongation	1
Assembly of the pre-replicative complex	1
Switching of origins to a post-replicative state	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
mismatch repair complex binding	3
recombinational repair	2
gamete generation	2
binding	2
ATP-dependent activity	2
DNA helicase activity	2
double-strand break repair	1
cellular response to stress	1
interstrand cross-link repair	1
regulation of protein stability	1
mismatch repair	1
DNA-templated DNA replication maintenance of fidelity	1
protein localization to chromosome	1
DNA metabolic process	1
DNA damage response	1
DNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
protein binding	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
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
intracellular membraneless organelle	1
protein-containing complex	1
MCM core complex	1
MCM complex	1

Protein interactions and networks

STRING

1813 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCM8	MCM9	Q9NXL9	921
MCM8	MCM6	Q14566	825
MCM8	MCM10	Q7L590	820
MCM8	PURA	Q00577	810
MCM8	MCM7	P33993	767
MCM8	CRLS1	Q9UJA2	756
MCM8	CDT1	Q9H211	721
MCM8	MCM5	P33992	714
MCM8	MCM4	P33991	704
MCM8	HFM1	A2PYH4	693
MCM8	STAG3	Q9UJ98	662
MCM8	HROB	Q8N3J3	658
MCM8	ETS1	P14921	646
MCM8	SYCE1	Q8N0S2	645
MCM8	E2F1	Q01094	623

IntAct

44 interactions, top by confidence:

A	B	Type	Score
MSH2	MSH3	psi-mi:“MI:0914”(association)	0.920
MCMBP	MCM3	psi-mi:“MI:0914”(association)	0.890
MLH1	PMS1	psi-mi:“MI:0914”(association)	0.830
MSH2	MCM9	psi-mi:“MI:0914”(association)	0.690
MCM8	MCMBP	psi-mi:“MI:0915”(physical association)	0.690
MCM9	MCM8	psi-mi:“MI:0915”(physical association)	0.640
GINS1	CDC45	psi-mi:“MI:0915”(physical association)	0.620
MCM8	MLH1	psi-mi:“MI:0915”(physical association)	0.560
MSH6	PCNA	psi-mi:“MI:0914”(association)	0.530
CAPN2	MYO9A	psi-mi:“MI:0914”(association)	0.530
KLHL40	CBX4	psi-mi:“MI:0914”(association)	0.530
PSG8	PEX7	psi-mi:“MI:0914”(association)	0.530
SKP2	DPYSL4	psi-mi:“MI:0914”(association)	0.530
LRRC27	HMOX1	psi-mi:“MI:0914”(association)	0.530
DONSON	CDC45	psi-mi:“MI:0914”(association)	0.500
MCM8	HSPA5	psi-mi:“MI:0915”(physical association)	0.400
MCM8	MRPS25	psi-mi:“MI:0915”(physical association)	0.400
FANCM	CDC45	psi-mi:“MI:0915”(physical association)	0.400
PB2	MCM8	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
MCM9	NOP56	psi-mi:“MI:0914”(association)	0.350
MCM9	PSMD14	psi-mi:“MI:0914”(association)	0.350
COPB2	ESYT2	psi-mi:“MI:0914”(association)	0.350
FKBP5	IFT56	psi-mi:“MI:0914”(association)	0.350
LMNB1	SUPT5H	psi-mi:“MI:0914”(association)	0.350
MIF	BLTP3B	psi-mi:“MI:0914”(association)	0.350

BioGRID (95): MCM8 (Affinity Capture-MS), MCM8 (Affinity Capture-MS), MCM8 (Affinity Capture-MS), MCM8 (Synthetic Growth Defect), MCM8 (Affinity Capture-MS), MCM8 (Affinity Capture-MS), MCM8 (Affinity Capture-MS), MCM8 (Affinity Capture-MS), MCM8 (Affinity Capture-MS), MCM8 (Affinity Capture-MS), MCM8 (Affinity Capture-MS), MCM8 (Affinity Capture-MS), MCM8 (Affinity Capture-MS), MCM8 (Affinity Capture-MS), MCM8 (Affinity Capture-MS)

ESM2 similar proteins: A0JN80, A2RV18, A2VE39, D2HRF1, D3ZG52, D3ZVK1, E1BMP7, G3GTP0, I0IUP3, O02697, P0DM58, P37202, P42338, P48736, P49717, P49917, Q08162, Q0P4R5, Q0V9Q6, Q0V9R3, Q0WPN0, Q17632, Q3EBC8, Q3V3E1, Q5F310, Q5R5N8, Q5R6L3, Q5R981, Q5U2P0, Q5U2Z5, Q5ZKG3, Q6GN11, Q6NQJ6, Q80VJ4, Q8BTF7, Q8BTI9, Q8C0L9, Q8C0S1, Q8CI75, Q8N1G2

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

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 60 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
Orc1 removal from chromatin	5	23.5×	1e-04
G2/M Checkpoints	5	17.7×	4e-04
DNA Repair	5	12.9×	1e-03
Cell Cycle, Mitotic	6	7.6×	3e-03
Cell Cycle	7	6.6×	2e-03
Cellular responses to stress	6	5.8×	9e-03
Cellular responses to stimuli	7	5.8×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
mismatch repair	6	74.8×	6e-08
DNA replication	6	19.1×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	5
Uncertain significance	107
Likely benign	10
Benign	12

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1049848	NM_032485.6(MCM8):c.2059C>T (p.Arg687Ter)	Pathogenic
161191	NM_032485.6(MCM8):c.446C>G (p.Pro149Arg)	Pathogenic
2068205	NM_032485.6(MCM8):c.1735dup (p.Met579fs)	Pathogenic
208810	NM_032485.6(MCM8):c.1954-1G>A	Pathogenic
208811	NM_032485.6(MCM8):c.1470_1471insTA (p.Leu491fs)	Pathogenic
2172278	NM_032485.6(MCM8):c.351_354del (p.Lys118fs)	Pathogenic
373125	NM_032485.6(MCM8):c.278_281del (p.Ile93fs)	Pathogenic
4278970	NM_032485.6(MCM8):c.1866_1867del (p.Ala623fs)	Pathogenic
812137	NM_032485.6(MCM8):c.925C>T (p.Arg309Ter)	Pathogenic
1214009	NM_032485.6(MCM8):c.1953+1G>C	Likely pathogenic
1328959	NM_032485.6(MCM8):c.482A>C (p.His161Pro)	Likely pathogenic
2084654	NM_032485.6(MCM8):c.1734-2A>G	Likely pathogenic
2419952	NM_032485.6(MCM8):c.790-2A>G	Likely pathogenic
2627933	NM_032485.6(MCM8):c.1404C>A (p.Cys468Ter)	Likely pathogenic

SpliceAI

3315 predictions. Top by Δscore:

Variant	Effect	Δscore
20:5950273:CTTA:C	donor_gain	1.0000
20:5950274:TTACT:T	donor_loss	1.0000
20:5950275:TACT:T	donor_loss	1.0000
20:5950276:A:AC	donor_gain	1.0000
20:5950276:AC:A	donor_loss	1.0000
20:5950276:ACTTT:A	donor_gain	1.0000
20:5950277:C:CA	donor_gain	1.0000
20:5950277:C:G	donor_loss	1.0000
20:5950277:CT:C	donor_gain	1.0000
20:5950277:CTT:C	donor_gain	1.0000
20:5950277:CTTT:C	donor_gain	1.0000
20:5950277:CTTTC:C	donor_gain	1.0000
20:5950880:GAGC:G	donor_gain	1.0000
20:5952010:GGA:G	acceptor_gain	1.0000
20:5952130:GATC:G	donor_gain	1.0000
20:5952133:C:G	donor_gain	1.0000
20:5952149:G:GT	donor_gain	1.0000
20:5952161:CTGG:C	donor_loss	1.0000
20:5952164:G:GG	donor_gain	1.0000
20:5952164:GT:G	donor_loss	1.0000
20:5952422:A:AG	acceptor_gain	1.0000
20:5952422:AGA:A	acceptor_loss	1.0000
20:5952423:G:GG	acceptor_gain	1.0000
20:5952423:GA:G	acceptor_gain	1.0000
20:5952423:GAA:G	acceptor_gain	1.0000
20:5952423:GAAC:G	acceptor_gain	1.0000
20:5952423:GAACA:G	acceptor_gain	1.0000
20:5954606:A:AG	acceptor_gain	1.0000
20:5954607:G:GG	acceptor_gain	1.0000
20:5955099:TAGG:T	acceptor_loss	1.0000

AlphaMissense

5516 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:5973161:G:A	G454R	1.000
20:5973161:G:C	G454R	1.000
20:5973162:G:A	G454E	1.000
20:5973180:A:T	K460I	1.000
20:5983105:C:A	A558D	1.000
20:5983115:T:A	N561K	1.000
20:5983115:T:G	N561K	1.000
20:5958604:G:A	G223R	0.999
20:5958604:G:C	G223R	0.999
20:5958604:G:T	G223W	0.999
20:5958605:G:A	G223E	0.999
20:5958617:G:C	R227P	0.999
20:5967537:G:A	G326E	0.999
20:5967558:G:A	G333E	0.999
20:5973069:G:A	G423D	0.999
20:5973153:T:C	L451P	0.999
20:5973162:G:T	G454V	0.999
20:5973171:G:A	G457D	0.999
20:5973176:G:A	G459R	0.999
20:5973176:G:C	G459R	0.999
20:5973177:G:A	G459E	0.999
20:5973179:A:C	K460Q	0.999
20:5973179:A:G	K460E	0.999
20:5973181:A:C	K460N	0.999
20:5973181:A:T	K460N	0.999
20:5973182:A:C	S461R	0.999
20:5973184:T:A	S461R	0.999
20:5973184:T:G	S461R	0.999
20:5977910:T:A	V477D	0.999
20:5977940:T:C	L487P	0.999

dbSNP variants (sampled 300 via entrez): RS1000086302 (20:5969174 T>C,G), RS1000136292 (20:5988554 G>A,T), RS1000221912 (20:5971920 A>C,T), RS1000278433 (20:5960352 C>G), RS1000293469 (20:5949977 G>A), RS1000313831 (20:5994983 A>C), RS1000328356 (20:5990791 CA>C), RS1000344225 (20:5966070 T>G), RS1000383074 (20:5997240 A>C,G), RS1000399608 (20:5965743 T>G), RS1000402164 (20:5949304 T>C), RS1000654491 (20:5983938 T>G), RS1000818030 (20:5959889 A>G), RS1000828923 (20:5972409 T>C), RS1000849062 (20:5955183 G>GAT)

Disease associations

OMIM: gene MIM:608187 | disease phenotypes: MIM:612885, MIM:610688

GenCC curated gene-disease

Disease	Classification	Inheritance
premature ovarian failure 10	Strong	Autosomal recessive
colorectal cancer	Limited	Autosomal dominant

Mondo (4): premature ovarian failure 10 (MONDO:0044776), azoospermia (MONDO:0100459), Joubert syndrome 6 (MONDO:0012539), colorectal cancer (MONDO:0005575)

Orphanet (1): Isolated Joubert syndrome (Orphanet:475)

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000027	Azoospermia
HP:0000786	Primary amenorrhea
HP:0000821	Hypothyroidism
HP:0008209	Premature ovarian insufficiency
HP:0008232	Elevated circulating follicle stimulating hormone level
HP:0008724	Hypoplasia of the ovary
HP:0008734	Decreased testicular size
HP:0011969	Elevated circulating luteinizing hormone level

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000401_1	Menopause (age at onset)	1.000000e-10
GCST000403_1	Menarche and menopause (age at onset)	1.000000e-21
GCST000656_5	HIV-1 viral setpoint	1.000000e-06
GCST001381_8	Menopause (age at onset)	1.000000e-73
GCST001949_4	Preeclampsia	2.000000e-06
GCST004988_442	Breast cancer	2.000000e-09
GCST005312_17	Menopause (age at onset)	5.000000e-09
GCST005312_45	Menopause (age at onset)	2.000000e-89
GCST005863_31	Menopause (age at onset)	7.000000e-11
GCST005863_35	Menopause (age at onset)	4.000000e-12
GCST006462_45	Uterine fibroids	2.000000e-10
GCST009158_7	Uterine fibroids	9.000000e-10
GCST90020092_2	Estradiol levels	5.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0000180	HIV-1 infection
EFO:0004697	estradiol measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D053713	Azoospermia	C12.100.500.430.380; C12.100.750.700.380; C12.200.294.430.380
C537689	Joubert syndrome 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases methylation	4
Benzo(a)pyrene	decreases expression, increases expression	3
Cyclosporine	affects expression, decreases expression	3
sodium arsenite	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
triphenyl phosphate	affects expression	1
4-biphenylamine	decreases reaction, decreases expression	1
lead acetate	increases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc chromate	increases abundance, decreases expression	1
cryptolepine	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
cupric chloride	increases expression	1
nickel sulfate	decreases expression	1
coumarin	increases phosphorylation	1
beta-methylcholine	affects expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
ICG 001	increases expression	1
incobotulinumtoxinA	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Dasatinib	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00114829	PHASE4	UNKNOWN	Preoperative Assessment of Colon Tumor
NCT00114842	PHASE4	COMPLETED	Magnetic Resonance (MR) Colonography With Fecal Tagging
NCT00114946	PHASE4	TERMINATED	A Study to Compare Two Avastin-Based Treatment Regimens for the Treatment of Metastatic Colorectal Cancer
NCT00122720	PHASE4	COMPLETED	The Effect of Darbepoetin Upon Rehabilitation for Colorectal Cancer Surgery
NCT00129870	PHASE4	TERMINATED	CONCEPT: Comparison of Oxaliplatin vs Conventional Methods With Calcium/Magnesium in First-Line Metastatic Colorectal Cancer
NCT00138060	PHASE4	COMPLETED	Toxicity/Benefit Ratio Optimization of Chemotherapy in Colorectal Cancer (CRC) Patients by Determination of Individual Genotypic Determinants
NCT00216424	PHASE4	TERMINATED	Capecitabine (Xeloda) and Radiation for Patients With Rectosigmoid Carcinoma
NCT00327093	PHASE4	TERMINATED	Elaboration of a Model for Predicting Efficacy of Monoclonal Antibodies (Cetuximab and Bevacizumab) in Patients With Colorectal Cancer and Liver Metastases
NCT00332943	PHASE4	COMPLETED	MR Colonography With Fecal Tagging. Barium vs. BariumFerumoxsil
NCT00441311	PHASE4	COMPLETED	Dissemination of Colorectal Cancer Screening to Primary Care Physicians
NCT00460837	PHASE4	WITHDRAWN	Comparison of Bowel Preparation in Virtual Colonoscopy (VC) - Patient Experience
NCT00473980	PHASE4	COMPLETED	Preoperative Non-steroidal Anti-inflammatory Drugs(NSAID) to Colorectal Cancer Patients
NCT00488904	PHASE4	COMPLETED	Omega-3 Fatty Acids and Postoperative Complications After Colorectal Surgery
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00502671	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) as Adjuvant Monotherapy in Patients With Colon Cancer.
NCT00559676	PHASE4	COMPLETED	Study of Biomarkers in Patients Undergoing Chemotherapy for Metastatic Colorectal Cancer
NCT00577031	PHASE4	COMPLETED	OBELIX Study: A Study of Avastin (Bevacizumab) in Combination With XELOX in Patients With Metastatic Cancer of the Colon or Rectum.
NCT00626054	PHASE4	COMPLETED	Comparison of Two Methods of Administration of a PEG Solution
NCT00812864	PHASE4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00868569	PHASE4	UNKNOWN	Transhepatic Arterial Chemotherapy (TAC) Versus Transcatheter Arterial Chemoembolization (TACE) Plus Folfox4 as the Treatment of Unresectable Liver Metastasis of Colorectal Cancer
NCT00868816	PHASE4	COMPLETED	Oxaliplatine Based Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: 8 Cycles Versus 12 Cycles
NCT00874406	PHASE4	UNKNOWN	Preoperative Transhepatic Arterial Chemotherapy (TAC) in the Treatment of Liver Metastasis of Resectable Colorectal Cancer
NCT00928928	PHASE4	COMPLETED	Oxidative Stress Markers in Open and Laparoscopic Colectomy for Cancer
NCT00942461	PHASE4	COMPLETED	Inflammatory Response in Laparoscopic and Open Colectomy
NCT01023633	PHASE4	UNKNOWN	OPTIMOX1 in Chinese mCRC Patients
NCT01271582	PHASE4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01315990	PHASE4	UNKNOWN	FOLFIRI in Combination With Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer Including a Regular Dermal Prophylaxis to Prevent Acneiforme Follicular Exanthema
NCT01493713	PHASE4	COMPLETED	Correlation Between RECIST, Morphologic Response by CT- Histopathologic Response in Hepatic Metastasis Secondary to Colorectal Cancer
NCT01609660	PHASE4	COMPLETED	Impact of Probiotics on the Intestinal Microbiota
NCT01641458	PHASE4	COMPLETED	Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients
NCT01689792	PHASE4	COMPLETED	A Multi-centre Study Comparing the Polyp Detection Rate of Two Different Types of Bowel Preparation: a 2-litre Solution (MOVIPREP®) Versus a Hyperosmotic and Stimulant Combined Low Volume Bowel Preparation (Sodium Picosulfate and Magnesium Citrate)
NCT01695772	PHASE4	COMPLETED	A Study of Bevacizumab Plus 5-Flurouracil (5-FU) Based Doublet Chemotherapy as Neoadjuvant Therapy for Participants With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer
NCT01695863	PHASE4	COMPLETED	Efficacy and Patient Satisfaction of Miralax and Gatorade Versus Movi Prep
NCT01706822	PHASE4	TERMINATED	Radial Reload Laparoscopic LAR Case Series
NCT01740947	PHASE4	TERMINATED	Does Administration of Antibiotics in Patients Undergoing Surgery for Colorectal Cancer Result in Less Complications and Better Prognosis?
NCT01831310	PHASE4	COMPLETED	Nutrition for Colorectal Cancer Patients and Neutrophil Functions
NCT01841294	PHASE4	UNKNOWN	NK Activity Modulation Induced by Intravenous Lidocaine During Colorectal Laparoscopic Surgery
NCT01959061	PHASE4	UNKNOWN	Efficacy and Safety of Raltitrexed-based Transarterial Chemoembolisation(TACE)for Colorectal Cancer Liver Metastases
NCT02032953	PHASE4	UNKNOWN	Enhancing the Anabolic Effect of Perioperative Nutrition With Insulin While Maintaining Normoglycemia
NCT02567331	PHASE4	COMPLETED	A Study of Capecitabine (Xeloda) in Patients With Metastatic Colorectal Cancer