CDC6

Summary

CDC6 (cell division cycle 6, HGNC:1744) is a protein-coding gene on chromosome 17q21.2, encoding Cell division control protein 6 homolog (Q99741). Involved in the initiation of DNA replication. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Cdc6, a protein essential for the initiation of DNA replication. This protein functions as a regulator at the early steps of DNA replication. It localizes in cell nucleus during cell cyle G1, but translocates to the cytoplasm at the start of S phase. The subcellular translocation of this protein during cell cyle is regulated through its phosphorylation by Cdks. Transcription of this protein was reported to be regulated in response to mitogenic signals through transcriptional control mechanism involving E2F proteins.

Source: NCBI Gene 990 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Meier-Gorlin syndrome 5 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 274 total — 1 likely-pathogenic
• Phenotypes (HPO): 64
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_001254

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1744
Approved symbol	CDC6
Name	cell division cycle 6
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000094804
Ensembl biotype	protein_coding
OMIM	602627
Entrez	990

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 16 protein_coding, 2 retained_intron

ENST00000209728, ENST00000473555, ENST00000577249, ENST00000580824, ENST00000582402, ENST00000648633, ENST00000649662, ENST00000908720, ENST00000908721, ENST00000936766, ENST00000936767, ENST00000936768, ENST00000936769, ENST00000936770, ENST00000936771, ENST00000936772, ENST00000936773, ENST00000936774

RefSeq mRNA: 1 — MANE Select: NM_001254 NM_001254

CCDS: CCDS11365

Canonical transcript exons

ENST00000209728 — 12 exons

Exon	Start	End
ENSE00000720428	40301468	40301608
ENSE00001058106	40300828	40301030
ENSE00001118352	40289408	40289598
ENSE00001118353	40293950	40294056
ENSE00001118354	40291469	40291668
ENSE00001118356	40293456	40293631
ENSE00001118357	40294364	40294503
ENSE00001118358	40295356	40295456
ENSE00001118359	40291058	40291339
ENSE00001118360	40296703	40296767
ENSE00003293006	40301912	40304657
ENSE00003837951	40287879	40288090

Expression profiles

Bgee: expression breadth ubiquitous, 186 present calls, max score 86.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.5366 / max 236.1674, expressed in 1425 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160707	18.3591	1424
160708	0.1775	81

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	86.28	gold quality
ganglionic eminence	UBERON:0004023	85.86	gold quality
embryo	UBERON:0000922	84.32	gold quality
secondary oocyte	CL:0000655	84.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.29	gold quality
rectum	UBERON:0001052	80.95	gold quality
stromal cell of endometrium	CL:0002255	80.90	gold quality
mucosa of transverse colon	UBERON:0004991	80.24	gold quality
bone marrow cell	CL:0002092	79.93	gold quality
vermiform appendix	UBERON:0001154	79.71	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.70	gold quality
bone marrow	UBERON:0002371	77.89	gold quality
right testis	UBERON:0004534	77.40	gold quality
oocyte	CL:0000023	76.01	gold quality
lymph node	UBERON:0000029	75.03	gold quality
left testis	UBERON:0004533	74.91	gold quality
esophagus mucosa	UBERON:0002469	74.79	gold quality
islet of Langerhans	UBERON:0000006	74.61	gold quality
testis	UBERON:0000473	74.26	gold quality
colonic epithelium	UBERON:0000397	73.46	gold quality
caecum	UBERON:0001153	73.05	gold quality
adrenal tissue	UBERON:0018303	72.93	gold quality
spleen	UBERON:0002106	71.90	gold quality
smooth muscle tissue	UBERON:0001135	69.83	gold quality
endometrium epithelium	UBERON:0004811	69.67	silver quality
gall bladder	UBERON:0002110	69.13	gold quality
duodenum	UBERON:0002114	68.85	gold quality
pancreas	UBERON:0001264	68.81	gold quality
right adrenal gland	UBERON:0001233	68.39	gold quality
prefrontal cortex	UBERON:0000451	67.88	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-99795	yes	355.85
E-MTAB-7052	yes	213.81
E-MTAB-7051	yes	82.84
E-ANND-3	yes	4.39
E-MTAB-6379	no	192.50
E-MTAB-6108	no	56.19

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ARID3A, CTNNB1, E2F1, E2F2, E2F3, E2F4, FOXM1, GATA1, HCFC1, HMGA1, KMT2E, MSC, POU2F1, RYBP, YBX1, YY1, ZBTB16, ZNF143

miRNA regulators (miRDB)

65 targeting CDC6, 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-1277-5P	100.00	73.95	5056
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-1284	99.67	73.56	1353
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-6073	99.60	70.36	793

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Nuclear organization of DNA replication initiation proteins (PMID:11779870)
• CHROMATIN CELLL CYCLE (PMID:11846807)
• downregulation in prostate cancer (PMID:12006585)
• HuCdc6 is cleaved by caspase 3 during apoptosis to prevent a wounded cell from replicating and to facilitate death (PMID:12151338)
• Results show that geminin, cdt1 and cdc6 are differentially regulated during megakaryocytic differentiation and suggest an active role of cdc6 in endomitosis. (PMID:12429841)
• Data show that human Cdc6 (HuCdc6) regulates the onset of mitosis, as overexpression of HuCdc6 in G(2) phase cells prevents entry into mitosis. (PMID:12554670)
• caspase-mediated cleavage of Cdc6 creates a truncated Cdc6 fragment that is retained in the nucleus and induces apoptosis (PMID:14517333)
• endogenous Cdc6 remains nuclear and chromatin bound throughout the entire S period (PMID:14749377)
• Cdc6 expression is regulated during megakaryocytic differentiation through transcriptional mechanisms involving a novel E2 box-GATA element. (PMID:15590906)
• Results further confirm the importance of CDC6 in malignant transformation and in the pathogenesis of cervical dysplasia. (PMID:15696126)
• Androgen receptor may play important role in onset of DNA synthesis in prostate cancer cells by regulating expression and stability of Cdc6, critically required for assembly of pre-replication complex. (PMID:15887248)
• initiation of DNA replication is regulated by p53 through Cdc6 protein stability (PMID:16055707)
• Cdc6 is not only required for G1 origin licensing, but is also crucial for proper S-phase DNA replication that is essential for DNA segregation during mitosis (PMID:16439999)
• Truncated Cdc6 proteins act as dominant-negative inhibitors of replication initiation and disrupt chromatin structure and/or induce DNA damage, leading to ATM/ATR kinase activation and p53-Bax-mediated apoptosis (PMID:16801388)
• These findings demonstrate an important and conserved role for Huwe1 in regulating Cdc6 abundance after DNA damage. (PMID:17567951)
• Cdc6 plays a key role in the sequential molecular events leading to repression of origin licensing and loss of proliferative capacity during execution of the differentiation programme. (PMID:17689530)
• hCdt1 and hCdc6 expression promote malignant behavior (PMID:18006835)
• deregulation of CDC6 expression in human cells poses a serious risk of carcinogenesis [review] (PMID:18048387)
• Data suggest that human Cdc6 functions in several pathways to control the cell proliferation and the cell death. (PMID:18259842)
• PP2A can be targeted in a calcium-regulated manner to Cdc6 via the PR70 subunit, where it plays a role in regulating protein phosphorylation and stability. (PMID:18397887)
• Cdc6 determines utilization of p21(WAF1/CIP1)-dependent damage checkpoint in S phase cells (PMID:18458079)
• rereplication-associated DNA damage triggers Cdt1 and Cdc6 ubiquitination and destruction; this pathway represents an evolutionarily conserved mechanism that minimizes the extent of rereplication (PMID:18617514)
• Polymorphism in the Cdc6 promoter is associated with hepatocellular carcinoma (PMID:18640135)
• The Cdc6 G1321A polymorphism is associated with decreased risk of cancer. (PMID:19101572)
• A hypothetical model whereby PTEN loss upregulates cell cycle genes such as cdc6 and cyclin E2 that in turn promote metastatic colonization at distant sites. (PMID:19107233)
• The Cdc6 protein, a key DNA replication initiation factor, contributes to the long-term maintenance of the S-phase checkpoint by anchoring the Rad3-Rad26 complex to chromatin. (PMID:19154794)
• Cdc6 mRNA and protein had low expressions in normal oral mucosa but were highly expressed in precancerous lesions and oral squamous cell carcinoma. (PMID:19189662)
• CDC6 may be one of the susceptibility genes that contribute to rapid decline in lung function despite smoking cessation in these patients with COPD. (PMID:19233139)
• The combination of st and deregulated cyclin E result in cooperative and coordinated activation of both an essential origin licensing factor, CDC6, and an activity required for origin firing, CDK2, resulting in progression from quiescence to S phase. (PMID:19321444)
• GCN5 specifically acetylates CDC6 at three lysine residues flanking its cyclin-docking motif, and this modification is crucial for the subsequent phosphorylation of the protein by Cyclin A-CDKs at a specific residue close to the acetylation site. (PMID:19343071)
• peak androgen receptor occupancy at the novel androgen-response element occurs during the G1/S phase concomitant with peak Cdc6 mRNA expression. (PMID:19520769)
• The expression of CDC6 was positively correlated with hMSH2 in cervical cancer. (PMID:19950599)
• Human CDC6 physically interacts with ATR, a crucial checkpoint kinase, in a manner that is stimulated by phosphorylation by Cdk and the CDC6-ATR interaction is conserved in Xenopus. (PMID:20048340)
• The CDC6 G1321A polymorphism may contribute to the risk of cervical cancer. (PMID:20606534)
• Norcantharidin can induce the degradation of Cdc6 in cancer cells to produce an anti-cancer effect. (PMID:20813683)
• Plk1-mediated phosphorylation of Cdc6 promotes the interaction of Cdc6 and Cdk1, leading to the attenuation of Cdk1 activity, release of separase, and subsequent anaphase progression. (PMID:21041660)
• Cdc6 expression is required for CDK2 chromatin association and kinase activation in stimulated primary human fibroblasts. (PMID:21088490)
• Phosphorylation of Cdc6 by polo-like kinase 1 (Plk1), one of the essential mitotic kinases, regulates mitotic exit. (PMID:21519187)
• A novel mechanism of cdc6 regulation in which ATR can have a central role in inhibiting the initiation of DNA replication by the regulation of cdc6. (PMID:22179839)
• The Cdc6 acts as a molecular switch at the E-cadherin locus, linking transcriptional repression to activation of replication. (PMID:22201124)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdc6	ENSDARG00000009942
mus_musculus	Cdc6	ENSMUSG00000017499
rattus_norvegicus	Cdc6	ENSRNOG00000027787
drosophila_melanogaster	Cdc6	FBGN0035918
caenorhabditis_elegans	cdc-6	WBGENE00000382

Paralogs (1): ORC1 (ENSG00000085840)

Protein

Protein identifiers

Cell division control protein 6 homolog — Q99741 (reviewed: Q99741)

Alternative names: CDC6-related protein, Cdc18-related protein, p62(cdc6)

All UniProt accessions (4): Q99741, J3KTI7, J3QLN7, J3QR52

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the initiation of DNA replication. Also participates in checkpoint controls that ensure DNA replication is completed before mitosis is initiated.

Subunit / interactions. Interacts with PCNA, ORC1, cyclin-CDK. Interacts with HUWE1. Interacts with ANKRD17. Interacts with GRWD1; origin binding of GRWD1 is dependent on CDC6. Interacts with CDT1; are mutually dependent on one another for loading MCM complexes onto chromatin. Interacts with TTC4. Interacts (via Cy motif) with CCNF; the interaction takes place during G2 and M phase. Interacts with CDH1.

Subcellular location. Nucleus. Cytoplasm.

Post-translational modifications. Ubiquitinated by the SCF(CCNF) E3 ubiquitin-protein ligase complex.

Disease relevance. Meier-Gorlin syndrome 5 (MGORS5) [MIM:613805] 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. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the CDC6/cdc18 family.

RefSeq proteins (1): NP_001245* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR015163	Cdc6_C	Domain
IPR016314	Cdc6/18	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR041664	AAA_16	Domain
IPR050311	ORC1/CDC6	Family
IPR054425	Cdc6_ORC1-like_ATPase_lid	Domain

Pfam: PF09079, PF13191, PF22606

UniProt features (26 total): modified residue 7, mutagenesis site 7, sequence variant 6, compositionally biased region 2, chain 1, region of interest 1, short sequence motif 1, binding site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
2CCH	X-RAY DIFFRACTION	1.7
4I5L	X-RAY DIFFRACTION	2.43
2CCI	X-RAY DIFFRACTION	2.7
4I5N	X-RAY DIFFRACTION	2.8
8S0E	ELECTRON MICROSCOPY	3.8
8RWV	ELECTRON MICROSCOPY	6.68
8HT7	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99741-F1	69.85	0.24

Functional residue map

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

Ligand- & substrate-binding residues (1): 202–209

Post-translational modifications (7): 106, 127, 419, 45, 54, 67, 74

Mutagenesis-validated functional residues (7):

Position	Phenotype
54	does not change protein stability after chx addition during mitosis; when associated with a-74 and a-106.
54	does not change protein stability after chx addition during mitosis; when associated with d-74 and d-106.
74	does not change protein stability after chx addition during mitosis; when associated with a-54 and a-106.
74	does not change protein stability after chx addition during mitosis; when associated with d-54 and d-106.
93–100	disrupts the interaction with ccnf. does not disrupt the interaction with cdh1. increases protein stability.
106	does not change protein stability after chx addition during mitosis; when associated with a-54 and a-74.
106	does not change protein stability after chx addition during mitosis; when associated with d-54 and d-74.

Function

Pathways and Gene Ontology

Reactome pathways

20 pathways

ID	Pathway
R-HSA-1362277	Transcription of E2F targets under negative control by DREAM complex
R-HSA-176187	Activation of ATR in response to replication stress
R-HSA-68689	CDC6 association with the ORC:origin complex
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-69017	CDK-mediated phosphorylation and removal of Cdc6
R-HSA-69205	G1/S-Specific Transcription
R-HSA-1538133	G0 and Early G1
R-HSA-1640170	Cell Cycle
R-HSA-453279	Mitotic G1 phase and G1/S transition
R-HSA-69002	DNA Replication Pre-Initiation
R-HSA-69052	Switching of origins to a post-replicative state
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: 610 (showing top): E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, E2F_Q4_01, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, KANG_DOXORUBICIN_RESISTANCE_UP, REACTOME_G1_S_SPECIFIC_TRANSCRIPTION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, E2F4DP1_01, GOBP_REGULATION_OF_PHOSPHORYLATION, FISCHER_G1_S_CELL_CYCLE, CROONQUIST_NRAS_SIGNALING_DN, GOBP_POSITIVE_REGULATION_OF_FIBROBLAST_PROLIFERATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_RESPONSE_TO_ANGIOTENSIN

GO Biological Process (15): DNA replication checkpoint signaling (GO:0000076), regulation of cyclin-dependent protein serine/threonine kinase activity (GO:0000079), DNA replication initiation (GO:0006270), traversing start control point of mitotic cell cycle (GO:0007089), negative regulation of DNA replication (GO:0008156), negative regulation of cell population proliferation (GO:0008285), regulation of mitotic metaphase/anaphase transition (GO:0030071), positive regulation of cytokinesis (GO:0032467), mitotic DNA replication checkpoint signaling (GO:0033314), positive regulation of fibroblast proliferation (GO:0048146), cell division (GO:0051301), positive regulation of chromosome segregation (GO:0051984), cellular response to vasopressin (GO:1904117), cellular response to angiotensin (GO:1904385), DNA replication (GO:0006260)

GO Molecular Function (7): nucleotide binding (GO:0000166), chromatin binding (GO:0003682), DNA replication origin binding (GO:0003688), ATP binding (GO:0005524), protein serine/threonine kinase binding (GO:0120283), protein binding (GO:0005515), ATP hydrolysis activity (GO:0016887)

GO Cellular Component (9): spindle pole (GO:0000922), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), intercellular bridge (GO:0045171), spindle midzone (GO:0051233), mitotic spindle (GO:0072686), spindle (GO:0005819)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
DNA Replication Pre-Initiation	2
Switching of origins to a post-replicative state	2
G1/S Transition	2
Mitotic G1 phase and G1/S transition	2
Cell Cycle, Mitotic	2
DNA Replication	2
Cell Cycle	2
G0 and Early G1	1
G2/M Checkpoints	1
Assembly of the pre-replicative complex	1
Synthesis of DNA	1
S Phase	1
Cell Cycle Checkpoints	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
spindle	3
DNA metabolic process	2
positive regulation of cell cycle process	2
cellular response to peptide hormone stimulus	2
binding	2
DNA integrity checkpoint signaling	1
cyclin-dependent protein serine/threonine kinase activity	1
regulation of protein serine/threonine kinase activity	1
DNA-templated DNA replication	1
positive regulation of G1/S transition of mitotic cell cycle	1
DNA replication	1
regulation of DNA replication	1
negative regulation of DNA metabolic process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
metaphase/anaphase transition of mitotic cell cycle	1
regulation of mitotic cell cycle phase transition	1
regulation of metaphase/anaphase transition of cell cycle	1
cytokinesis	1
regulation of cytokinesis	1
positive regulation of cell division	1
DNA replication checkpoint signaling	1
mitotic cell cycle	1
mitotic DNA integrity checkpoint signaling	1
mitotic G2/M transition checkpoint	1
positive regulation of cell population proliferation	1
fibroblast proliferation	1
regulation of fibroblast proliferation	1
cellular process	1
chromosome segregation	1
regulation of chromosome segregation	1
response to vasopressin	1
response to angiotensin	1
DNA biosynthetic process	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
sequence-specific double-stranded DNA binding	1
adenyl ribonucleotide binding	1

Protein interactions and networks

STRING

3546 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDC6	CDT1	Q9H211	998
CDC6	MCM3	P25205	993
CDC6	ORC6	Q9Y5N6	989
CDC6	MCM7	P33993	981
CDC6	CDC45	O75419	970
CDC6	MCM4	P33991	954
CDC6	CDC7	O00311	943
CDC6	CCNA2	P20248	941
CDC6	PPP2R3B	Q9Y5P8	934
CDC6	MCM5	P33992	923
CDC6	ORC4	O43929	922
CDC6	MCM10	Q7L590	922
CDC6	CCNA1	P78396	907
CDC6	DBF4	Q9UBU7	898
CDC6	E2F1	Q01094	895

IntAct

116 interactions, top by confidence:

A	B	Type	Score
TTC4	HSP90AB1	psi-mi:“MI:0914”(association)	0.750
CDC6	PLK1	psi-mi:“MI:0915”(physical association)	0.630
CDC6	PLK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.630
CDC6	PLK1	psi-mi:“MI:0914”(association)	0.630
CDC6	CDT1	psi-mi:“MI:0407”(direct interaction)	0.610
CDT1	CDC6	psi-mi:“MI:0915”(physical association)	0.610
CDKN1A	CDC6	psi-mi:“MI:0407”(direct interaction)	0.570
CDKN1A	CDC6	psi-mi:“MI:2364”(proximity)	0.570
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
MANSC1	KLRG2	psi-mi:“MI:0914”(association)	0.530
MAGEA10	POTEF	psi-mi:“MI:0914”(association)	0.530
TSPAN3	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
IL20RA	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
TGFBR2	PIK3R2	psi-mi:“MI:0914”(association)	0.530
FAM131B	AURKA	psi-mi:“MI:0914”(association)	0.530
TNFRSF8	DAPK3	psi-mi:“MI:0914”(association)	0.530
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
ISLR	BCKDK	psi-mi:“MI:0914”(association)	0.530
C1QTNF9B	PLOD3	psi-mi:“MI:0914”(association)	0.530
CDC6	CDK1	psi-mi:“MI:0915”(physical association)	0.520

BioGRID (215): CDC6 (Reconstituted Complex), CDC6 (Biochemical Activity), CDC6 (Biochemical Activity), CDC6 (Affinity Capture-MS), CDC6 (Affinity Capture-MS), CDC6 (Affinity Capture-MS), CDC6 (Affinity Capture-MS), CDC6 (Affinity Capture-MS), POLA1 (Co-fractionation), CDC6 (Affinity Capture-MS), CDKN1A (Co-localization), CDC6 (Affinity Capture-Western), CCNF (Affinity Capture-Western), CCNF (Reconstituted Complex), CDC6 (Biochemical Activity)

ESM2 similar proteins: A2AP18, A6QPL4, A8WFU8, F1QGZ6, F4JGP4, O75038, P28740, P49916, P70096, P79955, P97386, Q14680, Q14807, Q28GW8, Q2I6J1, Q2NL05, Q2R2P7, Q3B7N1, Q3V300, Q4KWH5, Q4KWH8, Q4R918, Q5E913, Q5I0E8, Q5REP4, Q5XI51, Q61846, Q62909, Q69Z98, Q6L512, Q6P3R1, Q6P549, Q6PCN7, Q6ZMV9, Q7SXA9, Q7ZYL5, Q86WJ1, Q8BYW1, Q8C0N1, Q8IWQ3

Diamond homologs: O74270, O82387, O89033, P41411, P54789, Q13415, Q58DC8, Q5N897, Q5SMU7, Q6BSE2, Q710E8, Q8I615, Q8W032, Q99741, Q9SU24, O16810, P54784, P54788, Q54RM2, Q80Z32, Q9JI69, Q9Z1N2, A1YVX4, A2A8L1, A2BIL7, A6H619, A8DZJ1, A9LMC0, B9RU15, D3ZD32, F4KBP5, G5EBZ4, O16102, O43918, O88379, O97159, P29375, P41229, P41230, P47156

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
PLK1	up-regulates	CDC6	phosphorylation
CyclinA2/CDK2	up-regulates	CDC6	phosphorylation
CyclinA2/CDK2	“down-regulates activity”	CDC6	phosphorylation
APC-c	“up-regulates activity”	CDC6	binding
CDK2	“down-regulates activity”	CDC6	phosphorylation
CDK2	up-regulates	CDC6	phosphorylation
SMARCB1	down-regulates	CDC6
YAP1	“up-regulates quantity by expression”	CDC6	“transcriptional regulation”
YAP/TAZ	“up-regulates quantity by expression”	CDC6	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 122 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of the pre-replicative complex	11	44.9×	3e-13
Activation of ATR in response to replication stress	10	37.6×	2e-11
G1/S Transition	10	29.1×	2e-10
Mitotic G1 phase and G1/S transition	12	27.6×	4e-12
Oncogene Induced Senescence	6	25.2×	8e-06
Orc1 removal from chromatin	11	24.5×	1e-10
DNA Replication Pre-Initiation	6	23.8×	1e-05
Assembly of the pre-replicative complex	11	19.1×	1e-09

GO biological processes:

GO term	Partners	Fold	FDR
DNA replication initiation	10	59.4×	4e-13
regulation of DNA-templated DNA replication initiation	5	50.1×	2e-05
positive regulation of fibroblast proliferation	5	14.1×	3e-03
cellular response to xenobiotic stimulus	6	13.8×	7e-04
DNA replication	7	11.0×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	158
Likely benign	71
Benign	12

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
369837	GRCh37/hg19 17q21.2(chr17:38456598-38456659)x1	Likely pathogenic

SpliceAI

1457 predictions. Top by Δscore:

Variant	Effect	Δscore
17:40289497:C:G	donor_gain	1.0000
17:40293450:TTCCA:T	acceptor_loss	1.0000
17:40293451:TCCA:T	acceptor_loss	1.0000
17:40293452:CCAG:C	acceptor_loss	1.0000
17:40293453:CAGA:C	acceptor_loss	1.0000
17:40293454:A:AG	acceptor_gain	1.0000
17:40293454:AGAA:A	acceptor_loss	1.0000
17:40293454:AGAAG:A	acceptor_gain	1.0000
17:40293455:G:GG	acceptor_gain	1.0000
17:40293455:GA:G	acceptor_gain	1.0000
17:40293455:GAA:G	acceptor_gain	1.0000
17:40293455:GAAG:G	acceptor_loss	1.0000
17:40293455:GAAGG:G	acceptor_gain	1.0000
17:40293627:ATGAT:A	donor_gain	1.0000
17:40293628:TGAT:T	donor_gain	1.0000
17:40293629:GAT:G	donor_gain	1.0000
17:40293629:GATG:G	donor_gain	1.0000
17:40293630:AT:A	donor_gain	1.0000
17:40293631:TG:T	donor_loss	1.0000
17:40293632:G:GG	donor_gain	1.0000
17:40293632:GTA:G	donor_loss	1.0000
17:40293633:T:A	donor_loss	1.0000
17:40293996:G:GT	donor_gain	1.0000
17:40294028:GC:G	donor_gain	1.0000
17:40294029:C:G	donor_gain	1.0000
17:40295342:T:G	acceptor_gain	1.0000
17:40295351:T:A	acceptor_gain	1.0000
17:40295354:A:AC	acceptor_loss	1.0000
17:40295354:A:AG	acceptor_gain	1.0000
17:40295355:G:GG	acceptor_gain	1.0000

AlphaMissense

3656 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:40291631:A:T	K208I	0.998
17:40295402:C:A	A377D	0.998
17:40291603:T:G	Y199D	0.997
17:40291628:G:A	G207E	0.997
17:40293494:C:G	C233W	0.997
17:40293967:A:T	E285V	0.997
17:40294020:T:A	W303R	0.997
17:40294020:T:C	W303R	0.997
17:40294369:G:C	A317P	0.997
17:40294374:T:A	N318K	0.997
17:40294374:T:G	N318K	0.997
17:40296707:G:C	A397P	0.997
17:40291533:G:C	R175S	0.996
17:40291533:G:T	R175S	0.996
17:40291601:T:C	L198P	0.996
17:40291622:G:A	G205E	0.996
17:40291634:C:T	T209I	0.996
17:40293964:A:C	D284A	0.996
17:40293964:A:T	D284V	0.996
17:40293967:A:C	E285A	0.996
17:40293979:T:C	L289P	0.996
17:40294364:G:A	G315D	0.996
17:40294370:C:A	A317D	0.996
17:40291630:A:C	K208Q	0.995
17:40291632:A:C	K208N	0.995
17:40291632:A:T	K208N	0.995
17:40293963:G:C	D284H	0.995
17:40294014:T:C	F301L	0.995
17:40294016:T:A	F301L	0.995
17:40294016:T:G	F301L	0.995

dbSNP variants (sampled 300 via entrez): RS1000130983 (17:40290617 G>A,C,T), RS1000245984 (17:40290356 G>A), RS1000465945 (17:40292215 G>C), RS1000581552 (17:40291987 T>C), RS1000879805 (17:40290985 A>C,G), RS1001202591 (17:40300028 A>G,T), RS1001272328 (17:40292749 G>A), RS1001353609 (17:40291444 A>C,G), RS1001441139 (17:40299863 T>C), RS1001454126 (17:40286638 G>A), RS1001615444 (17:40292446 C>T), RS1002306961 (17:40301299 G>A), RS1002575891 (17:40287774 G>A), RS1002639085 (17:40303023 A>G), RS1002640141 (17:40295922 T>C)

Disease associations

OMIM: gene MIM:602627 | disease phenotypes: MIM:613805

GenCC curated gene-disease

Disease	Classification	Inheritance
Meier-Gorlin syndrome 5	Definitive	Autosomal recessive
Meier-Gorlin syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Meier-Gorlin syndrome 5	Limited	AR

Mondo (3): Meier-Gorlin syndrome 5 (MONDO:0013432), microcephaly (MONDO:0001149), Meier-Gorlin syndrome (MONDO:0016817)

Orphanet (1): Ear-patella-short stature syndrome (Orphanet:2554)

HPO phenotypes

64 total (30 of 64 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000039	Epispadias
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000059	Hypoplastic labia majora
HP:0000060	Clitoral hypoplasia
HP:0000064	Hypoplastic labia minora
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000193	Bifid uvula
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000325	Triangular face
HP:0000327	Hypoplasia of the maxilla
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000356	Abnormality of the outer ear
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000385	Small earlobe
HP:0000413	Atresia of the external auditory canal
HP:0000772	Abnormal rib morphology
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001328	Specific learning disability
HP:0001363	Craniosynostosis
HP:0001382	Joint hypermobility

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008916_85	Asthma	2.000000e-12

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
C538012	Meier-Gorlin syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2311228 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, increases expression, decreases reaction	5
bisphenol A	decreases expression, increases expression	4
Fluorouracil	decreases expression, increases expression, affects cotreatment, affects expression	4
Resveratrol	increases expression, decreases expression, affects cotreatment	3
Benzo(a)pyrene	decreases expression, increases expression, increases methylation	3
Quercetin	affects cotreatment, increases expression, decreases expression	3
Tretinoin	decreases expression	3
Cyclosporine	increases expression	3
Aflatoxin B1	affects expression, decreases expression, increases expression	3
methylselenic acid	affects expression, decreases expression	2
ochratoxin A	affects cotreatment, decreases expression	2
picoxystrobin	decreases expression, increases expression	2
Arsenic Trioxide	decreases reaction, increases expression, affects reaction	2
Acetaminophen	increases expression, decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Antimycin A	decreases expression, increases expression	2
Cisplatin	decreases expression, increases expression	2
Niclosamide	decreases expression	2
Parathion	increases expression, affects cotreatment	2
Plant Extracts	increases expression, affects expression, affects reaction, affects cotreatment	2
Rotenone	decreases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Lithium Chloride	increases expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
lasiocarpine	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2317267	Binding	Inhibition of cdc6 (unknown origin) at 10 uM	Alkylsulfanyl-1,2,4-triazoles, a new class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04569149	Not specified	RECRUITING	Primordial Dwarfism Registry
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.