CDT1

Summary

CDT1 (chromatin licensing and DNA replication factor 1, HGNC:24576) is a protein-coding gene on chromosome 16q24.3, encoding DNA replication factor Cdt1 (Q9H211). Required for both DNA replication and mitosis. It is a common-essential gene (DepMap: required in 99.8% of cancer cell lines).

The protein encoded by this gene is involved in the formation of the pre-replication complex that is necessary for DNA replication. The encoded protein can bind geminin, which prevents replication and may function to prevent this protein from initiating replication at inappropriate origins. Phosphorylation of this protein by cyclin A-dependent kinases results in degradation of the protein.

Source: NCBI Gene 81620 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Meier-Gorlin syndrome 4 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 547 total — 19 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 59
• Cancer dependency (DepMap): dependent in 99.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_030928

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24576
Approved symbol	CDT1
Name	chromatin licensing and DNA replication factor 1
Location	16q24.3
Locus type	gene with protein product
Status	Approved
Aliases	DUP, RIS2
Ensembl gene	ENSG00000167513
Ensembl biotype	protein_coding
OMIM	605525
Entrez	81620

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000301019, ENST00000562747, ENST00000569140, ENST00000929785

RefSeq mRNA: 1 — MANE Select: NM_030928 NM_030928

CCDS: CCDS32510

Canonical transcript exons

ENST00000301019 — 10 exons

Exon	Start	End
ENSE00001177046	88807281	88807482
ENSE00001177051	88807051	88807203
ENSE00001177060	88806486	88806674
ENSE00001177067	88806021	88806121
ENSE00001294501	88804545	88804667
ENSE00001297592	88808115	88809258
ENSE00001309555	88803789	88804059
ENSE00003462645	88805724	88805869
ENSE00003465616	88805440	88805637
ENSE00003580400	88804762	88804898

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 96.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 79.8445 / max 1410.6149, expressed in 1570 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155555	79.8445	1570

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of paranasal sinus	UBERON:0005030	96.23	silver quality
superficial temporal artery	UBERON:0001614	95.19	silver quality
oocyte	CL:0000023	93.12	gold quality
endometrium epithelium	UBERON:0004811	90.89	silver quality
gingival epithelium	UBERON:0001949	89.53	silver quality
secondary oocyte	CL:0000655	89.00	gold quality
ventricular zone	UBERON:0003053	88.71	gold quality
ganglionic eminence	UBERON:0004023	86.21	gold quality
gingiva	UBERON:0001828	85.28	silver quality
mucosa of transverse colon	UBERON:0004991	85.22	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.40	gold quality
trabecular bone tissue	UBERON:0002483	82.11	gold quality
bone marrow	UBERON:0002371	82.04	gold quality
embryo	UBERON:0000922	81.54	gold quality
stromal cell of endometrium	CL:0002255	79.87	gold quality
epithelium of nasopharynx	UBERON:0001951	79.62	silver quality
germinal epithelium of ovary	UBERON:0001304	79.58	gold quality
esophagus mucosa	UBERON:0002469	76.83	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.77	gold quality
colonic mucosa	UBERON:0000317	75.79	gold quality
mucosa of sigmoid colon	UBERON:0004993	75.19	silver quality
esophagus squamous epithelium	UBERON:0006920	74.87	silver quality
lower esophagus mucosa	UBERON:0035834	74.18	gold quality
amniotic fluid	UBERON:0000173	73.68	silver quality
squamous epithelium	UBERON:0006914	73.24	silver quality
cardia of stomach	UBERON:0001162	72.33	gold quality
bone marrow cell	CL:0002092	72.11	gold quality
placenta	UBERON:0001987	72.11	gold quality
mammary duct	UBERON:0001765	72.10	gold quality
epithelium of esophagus	UBERON:0001976	71.08	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	17.74
E-ANND-3	yes	6.16

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F2, E2F3, E2F4, KLF5, SMARCA5

miRNA regulators (miRDB)

19 targeting CDT1, 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-3925-3P	100.00	69.95	1237
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-4753-5P	99.54	68.51	1356
HSA-MIR-6797-3P	99.17	66.94	668
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-6076	98.61	65.69	637
HSA-MIR-4266	98.53	67.29	1035
HSA-MIR-8089	97.74	66.21	1698
HSA-MIR-4667-5P	97.61	66.67	1683
HSA-MIR-96-3P	97.47	68.03	839
HSA-MIR-1225-3P	97.29	64.60	876
HSA-MIR-4296	96.35	63.55	1233
HSA-MIR-1291	96.28	65.89	1224
HSA-MIR-6775-3P	95.76	65.91	982
HSA-MIR-6879-3P	93.93	64.00	759

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• human CDT1 is essential for DNA replication and chromatin licensing (PMID:11896191)
• Results show that geminin, cdt1 and cdc6 are differentially regulated during megakaryocytic differentiation and suggest an active role of cdc6 in endomitosis. (PMID:12429841)
• SCF(Skp2)-mediated ubiquitination pathway may play an important role in the cell cycle-dependent Cdt1 degradation in mammalian cells. (PMID:12840033)
• Cdt1 function is negatively regulated by the Cdk phosphorylation independent of geminin binding (PMID:14993212)
• Cdt1 is phosphorylated and its degradation induced by Cdk2 and Cdk4 (PMID:15004027)
• Geminin is both a negative and positive regulator of pre-replicative complex formation in human cells, playing a positive role in allowing CDT1 accumulation in G2-M (PMID:15257290)
• in proliferating HeLa cells geminin and Cdt1 are co-expressed during a relatively short time at the G(1)-to-S phase transition; Cdt1 is rapidly degraded early in S phase, but geminin remains bound to the chromatin sites (PMID:15284237)
• a Skp2-independent pathway that requires the N-terminal 32 residues of Cdt1 is critical for the degradation of Cdt1 in S phase- this degradation is necessary for the optimum progression of cells through S phase (PMID:15855168)
• Cdt1 overexpression contributes to tumorigenecity by causing genomic instability in transgenic p53 knockout mice. (PMID:16261166)
• Cdt1 expression is severely downregulated upon differentiation of Caco-2 cells, an in vitro model of intestinal epithelial differentiation. (PMID:16273206)
• PCNA is involved in mediating Cdt1 degradation by the Cul4-Ddb1 ligase in response to DNA damage. (PMID:16407242)
• Data from several different systems strongly indicate that unregulated Cdt1 overexpression at pathophysiological levels can induce chromosomal damage other than rereplication in non-transformed cells. (PMID:16835273)
• L2DTL and PCNA interact with CUL4/DDB1 complexes and are involved in CDT1 degradation after DNA damage. (PMID:16861906)
• Results suggest that DDB1 prevents DNA lesions from accumulating in replicating human cells, in part by regulating Cdt1 degradation. (PMID:16940174)
• These studies uncover diverse substrate receptors for Cul4 and identify Cdt2 as a conserved component of the Cul4-Ddb1 E3 that is essential to destroy Cdt1 and ensure proper cell cycle regulation of DNA replication. (PMID:16949367)
• Findings suggest that the CDT1 838G/A and GMNN 387C/A polymorphisms may not play a major role in the etiology of breast cancer, but CDT1 variant may have a potential role only in genetically susceptible women. (PMID:17029205)
• DTL promotes genomic stability through two distinct mechanisms. First, it is an essential component of the CUL4-DDB1 complex that controls CDT1 levels, thereby preventing rereplication. Second, it is required for the early G2/M checkpoint. (PMID:17085480)
• we discuss how these dynamic Cdt1-chromatin interactions and the local recruitment of Geminin onto origins of replication by Cdt1 may provide a tight control of the licensing process in time and in space. (PMID:17598984)
• hCdt1 and hCdc6 expression promote malignant behavior (PMID:18006835)
• Human Cdt1-binding proteins were identified by a combination of Cdt1 affinity chromatography and liquid chromatography and tandem mass spectrometry analysis. (PMID:18162579)
• exogenous Cdt1 induces re-replication by de-repressing endogenous Cdt1 through the titration of PCNA and cyclin; Cdt1 lacking the evolutionarily conserved region that interacts with MCM2-7 is capable of inducing re-replication (PMID:18184650)
• These results suggested that, at least in vitro, oleic acid-containing cell membranes of the lipid bilayer inhibit Cdt1-geminin complex formation by binding to Cdt1 and thereby liberating Cdt1 from inhibition by geminin. (PMID:18288374)
• Cdt1 and Geminin expression is deregulated in human tumor specimens and may represent novel markers useful for cancer diagnosis and prognosis. (PMID:18508524)
• 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)
• PcG complex 1, involving Rae28 and Cdt1, supports the activity of hematopoietic stem cells by enhancing cycling capability and hematopoietic activity through direct regulation of Geminin (PMID:18650381)
• Cdt1, with its two opposing regulatory binding factors MCM9 and geminin, appears to be a major platform on the pre-replication complexes to integrate cell-cycle signals. (PMID:18657502)
• HBO1 associates with replication origins specifically during the G1 phase of the cell cycle in a manner that depends on the replication licensing factor Cdt1, but is independent of the Cdt1 repressor Geminin. (PMID:18832067)
• chromatin-bound CDT1 is first stabilized and subsequently displaced by CDC7 activity, thereby ensuring the timely execution of DNA replication (PMID:19054765)
• Cdt1 undergoes acetylation and is reversibly deacetylated by HDAC11 (PMID:19276081)
• Data show that the Cdt1:Geminin complex can exist in two distinct forms, a “permissive” heterotrimer and an “inhibitory” heterohexamer. (PMID:19906994)
• Cdt1 degradation following UV irradiation occurs rapidly at damaged sites due to PCNA chromatin loading and the recruitment of Cdt1 and CRL4(Cdt2), before DNA damage repair is completed (PMID:20929861)
• Cdt1 promote MCM loading in vivo involves the stimulation of large-scale chromatin decondensation to allow access to the underlying DNA substrate. (PMID:20980834)
• Results indicate that the interaction between hCdt1 and hMcm6 through their interacting domains is key for hCdt1 in facilitating the MCM hetero-hexamer to load onto chromatin for replication licensing. (PMID:21099365)
• in human cancer cells, RBX1 silencing causes the accumulation of DNA replication licensing proteins CDT1 and ORC1, leading to DNA double-strand breaks, DDR, G(2) arrest, and, eventually, aneuploidy (PMID:21115485)
• Cdt1 is recruited onto damaged sites in G1 phase cells, within seconds of DNA damage induction by ultraviolet laser (PMID:21224399)
• study reports that UBCH8 and UBE2G1 and UBE2G2 cooperate with CRL4Cdt2 in promoting the polyubiquitylation and subsequent degradation of p21 and Cdt1, respectively (PMID:21628527)
• The over-expression of geminin and cdt1 may play an important role in pathogenesis of acute leukemia. (PMID:21729526)
• Studies suggest that DNA damage-induced ubiquitination or sumoylation of PCNA prevents CRL4Cdt2-dependent degradation by inhibiting binding of Cdt1 to PCNA. (PMID:21846465)
• JNK1 phosphorylation of Cdt1 inhibits recruitment of HBO1 histone acetylase and blocks replication licensing in response to stress (PMID:21856198)
• findings support a model in which MAP kinase activity in G(2) promotes reaccumulation of a low-activity Cdt1 isoform after replication is complete. (PMID:21930785)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdt1	ENSDARG00000051854
mus_musculus	Cdt1	ENSMUSG00000006585
rattus_norvegicus	Cdt1	ENSRNOG00000013970
drosophila_melanogaster	dup	FBGN0000996
caenorhabditis_elegans	cdt-1	WBGENE00000413

Protein

Protein identifiers

DNA replication factor Cdt1 — Q9H211 (reviewed: Q9H211)

Alternative names: Double parked homolog

All UniProt accessions (2): Q9H211, H3BSY1

UniProt curated annotations — full annotation on UniProt →

Function. Required for both DNA replication and mitosis. DNA replication licensing factor, required for pre-replication complex assembly. Cooperates with CDC6 and the origin recognition complex (ORC) during G1 phase of the cell cycle to promote the loading of the mini-chromosome maintenance (MCM) complex onto DNA to generate pre-replication complexes (pre-RC). Required also for mitosis by promoting stable kinetochore-microtubule attachments. Potential oncogene.

Subunit / interactions. Interacts with GMNN; the interaction inhibits binding of the MCM complex to origins of replication. Interacts with MCM6. Interacts with CDC6; are mutually dependent on one another for loading MCM complexes onto chromatin. Interacts with PCNA. Interacts with LRWD1 during G1 phase and during mitosis. Interacts with NDC80 subunit of the NDC80 complex; leading to kinetochore localization. Interacts with GRWD1; origin binding of GRWD1 is dependent on CDT1. Interacts with KAT7. Interacts with ubiquitin-binding protein FAF1; the interaction is likely to promote CDT1 degradation.

Subcellular location. Nucleus. Chromosome. Centromere. Kinetochore.

Post-translational modifications. Two independent E3 ubiquitin ligase complexes, SCF(SKP2) and the DCX(DTL) complex, mediated CDT1 degradation in S phase. Ubiquitinated by the DCX(DTL) complex, in response to DNA damage, leading to its degradation. Ubiquitination by the DCX(DTL) complex is necessary to ensure proper cell cycle regulation and is PCNA-dependent: interacts with PCNA via its PIP-box, while the presence of the containing the ‘K+4’ motif in the PIP box, recruit the DCX(DTL) complex, leading to its degradation. Phosphorylation at Thr-29 by CDK2 targets CDT1 for ubiquitination by SCF(SKP2) E3 ubiquitin ligase and subsequent degradation. The interaction with GMNN protects it against ubiquitination. Deubiquitinated by USP37. Ubiquitinated and degraded by the SCF(FBXO31) complex during the G2 phase to prevent re-replication. Phosphorylation by cyclin A-dependent kinases at Thr-29 targets CDT1 for ubiquitynation by SCF(SKP2) E3 ubiquitin ligase and subsequent degradation. Phosphorylated at Thr-29 by MAPK8/JNK1, which blocks replication licensing in response to stress. Binding to GMNN is not affected by phosphorylation.

Disease relevance. Meier-Gorlin syndrome 4 (MGORS4) [MIM:613804] 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.

Domain organisation. The PIP-box K+4 motif mediates both the interaction with PCNA and the recruitment of the DCX(DTL) complex: while the PIP-box interacts with PCNA, the presence of the K+4 submotif, recruits the DCX(DTL) complex, leading to its ubiquitination.

Induction. Induced by E2F transcription factors.

Similarity. Belongs to the Cdt1 family.

RefSeq proteins (1): NP_112190* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR014939	CDT1_Gemini-bd-like	Domain
IPR032054	Cdt1_C	Domain
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR038090	Cdt1_C_WH_dom_sf	Homologous_superfamily
IPR045173	Cdt1	Family

Pfam: PF08839, PF16679

UniProt features (47 total): sequence variant 11, helix 10, modified residue 6, region of interest 5, compositionally biased region 4, strand 3, mutagenesis site 2, turn 2, short sequence motif 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
2WVR	X-RAY DIFFRACTION	3.3
6QCG	X-RAY DIFFRACTION	3.4
8S0E	ELECTRON MICROSCOPY	3.8
8S0F	ELECTRON MICROSCOPY	4.1
8RWV	ELECTRON MICROSCOPY	6.68
2LE8	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H211-F1	74.51	0.35

Functional residue map

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

Post-translational modifications (6): 29, 31, 93, 318, 380, 394

Mutagenesis-validated functional residues (2):

Position	Phenotype
68–70	abolishes binding of cyclin a-dependent protein kinases.
170	alters interaction with gmnn.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
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-69205	G1/S-Specific Transcription
R-HSA-1640170	Cell Cycle
R-HSA-453279	Mitotic G1 phase and G1/S transition
R-HSA-69002	DNA Replication Pre-Initiation
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

MSigDB gene sets: 402 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, GOBP_ATTACHMENT_OF_SPINDLE_MICROTUBULES_TO_KINETOCHORE, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, WANG_CLIM2_TARGETS_UP, REACTOME_G1_S_SPECIFIC_TRANSCRIPTION, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, GOBP_CELL_CYCLE_DNA_REPLICATION, FISCHER_G1_S_CELL_CYCLE, GOBP_CHROMOSOME_LOCALIZATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, MITSIADES_RESPONSE_TO_APLIDIN_DN

GO Biological Process (16): DNA replication checkpoint signaling (GO:0000076), mitotic cell cycle (GO:0000278), regulation of DNA-templated DNA replication initiation (GO:0030174), regulation of nuclear cell cycle DNA replication (GO:0033262), positive regulation of DNA replication (GO:0045740), negative regulation of cell cycle (GO:0045786), cell division (GO:0051301), attachment of mitotic spindle microtubules to kinetochore (GO:0051315), DNA replication preinitiation complex assembly (GO:0071163), response to sorbitol (GO:0072708), mitotic DNA replication initiation (GO:1902975), mitotic pre-replicative complex assembly (GO:1902985), negative regulation of DNA-templated DNA replication (GO:2000104), DNA replication (GO:0006260), positive regulation of chromatin binding (GO:0035563), positive regulation of DNA-templated DNA replication (GO:2000105)

GO Molecular Function (4): DNA binding (GO:0003677), chromatin binding (GO:0003682), DNA polymerase binding (GO:0070182), protein binding (GO:0005515)

GO Cellular Component (6): kinetochore (GO:0000776), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear body (GO:0016604), chromosome, centromeric region (GO:0000775), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
DNA Replication Pre-Initiation	2
G1/S Transition	2
Cell Cycle, Mitotic	2
DNA Replication	2
Switching of origins to a post-replicative state	1
Synthesis of DNA	1
Mitotic G1 phase and G1/S transition	1
S Phase	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated DNA replication	4
mitotic cell cycle process	3
intracellular membraneless organelle	3
cell cycle	2
nuclear DNA replication	2
mitotic DNA replication	2
DNA-templated DNA replication	2
binding	2
DNA integrity checkpoint signaling	1
mitotic nuclear division	1
DNA replication initiation	1
regulation of cell cycle process	1
DNA replication	1
regulation of DNA replication	1
positive regulation of DNA metabolic process	1
negative regulation of cellular process	1
regulation of cell cycle	1
cellular process	1
mitotic metaphase chromosome alignment	1
attachment of spindle microtubules to kinetochore	1
cell cycle process	1
protein-DNA complex assembly	1
response to carbohydrate	1
nuclear cell cycle DNA replication initiation	1
pre-replicative complex assembly involved in nuclear cell cycle DNA replication	1
negative regulation of DNA replication	1
DNA metabolic process	1
DNA biosynthetic process	1
chromatin binding	1
positive regulation of binding	1
positive regulation of DNA replication	1
nucleic acid binding	1
enzyme binding	1
condensed chromosome, centromeric region	1
supramolecular complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nucleoplasm	1
chromosomal region	1

Protein interactions and networks

STRING

2542 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDT1	CDC6	Q99741	998
CDT1	MCM6	Q14566	986
CDT1	ORC6	Q9Y5N6	982
CDT1	GMNN	O75496	982
CDT1	MCM7	P33993	981
CDT1	DTL	Q9NZJ0	980
CDT1	CDC45	O75419	964
CDT1	DDB1	Q16531	949
CDT1	MCM10	Q7L590	945
CDT1	KAT7	O95251	941
CDT1	MCM3	P25205	936
CDT1	GRWD1	Q9BQ67	935
CDT1	MCM4	P33991	931
CDT1	ORC4	O43929	930
CDT1	MCM5	P33992	917

IntAct

62 interactions, top by confidence:

A	B	Type	Score
CDT1	GMNN	psi-mi:“MI:0915”(physical association)	0.970
GMNN	CDT1	psi-mi:“MI:0915”(physical association)	0.970
CDT1	GMNN	psi-mi:“MI:0407”(direct interaction)	0.970
GMNN	CDT1	psi-mi:“MI:0407”(direct interaction)	0.970
GMNN	CDT1	psi-mi:“MI:2364”(proximity)	0.970
CDT1	GMNN	psi-mi:“MI:0914”(association)	0.970
CDK1	CCNB2	psi-mi:“MI:0914”(association)	0.840
GMNN	MCIDAS	psi-mi:“MI:0914”(association)	0.770
MCM6	CDT1	psi-mi:“MI:0915”(physical association)	0.660
CDT1	MCM6	psi-mi:“MI:0407”(direct interaction)	0.660
CCNA2	GMNN	psi-mi:“MI:0914”(association)	0.640
CDK2	GMNN	psi-mi:“MI:0914”(association)	0.640
CDC6	CDT1	psi-mi:“MI:0407”(direct interaction)	0.610
CDT1	CDC6	psi-mi:“MI:0915”(physical association)	0.610

BioGRID (209): FBXO31 (Affinity Capture-Western), CDT1 (Affinity Capture-Western), CDT1 (Reconstituted Complex), CDT1 (Biochemical Activity), GMNN (Affinity Capture-Western), CDT1 (Affinity Capture-Western), CDT1 (Affinity Capture-MS), CDT1 (Affinity Capture-MS), CDT1 (Affinity Capture-MS), MAPK9 (Affinity Capture-Western), MAPK14 (Affinity Capture-Western), CDT1 (Biochemical Activity), MCM2 (Reconstituted Complex), PCNA (Reconstituted Complex), DTL (Reconstituted Complex)

ESM2 similar proteins: A1L188, A2AMZ4, A2XK00, A7YY73, B4FGS2, B4FTR7, B8B624, C0HAV3, C5E268, G2TRP6, O13973, O75012, O95159, O95872, Q0VDN7, Q12894, Q28H71, Q2YDD3, Q3SZA2, Q3SZW4, Q3U0S6, Q3UJV1, Q49AH0, Q4G012, Q5FVV3, Q5U509, Q5U651, Q61858, Q6ASS9, Q6P0I6, Q756Q5, Q7S4Y4, Q7XAM0, Q7XK12, Q8BGD8, Q8BGX2, Q8CC36, Q8VED2, Q96BP2, Q96C34

Diamond homologs: Q8R4E9, Q9H211, Q9I9A7

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
CDT1	“up-regulates activity”	MCM	binding
GMNN	“down-regulates activity”	CDT1	binding
CDT1	“up-regulates activity”	MCM2	binding
CDT1	“up-regulates activity”	CDT1	binding
SKP2	“down-regulates quantity by destabilization”	CDT1	binding
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	CDT1	polyubiquitination
Cullin4-RBX1-DDB1	“down-regulates quantity by destabilization”	CDT1	polyubiquitination
MAPK8	“up-regulates quantity by stabilization”	CDT1	phosphorylation
p38	“up-regulates quantity by stabilization”	CDT1	phosphorylation
MAPK8	“down-regulates activity”	CDT1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 30 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	6	97.9×	5e-09
Activation of ATR in response to replication stress	5	75.1×	2e-07
Switching of origins to a post-replicative state	5	75.1×	2e-07
G1/S Transition	5	58.3×	7e-07
Orc1 removal from chromatin	6	53.5×	1e-07
Mitotic G1 phase and G1/S transition	5	46.0×	2e-06
Assembly of the pre-replicative complex	5	34.8×	5e-06
G2/M Checkpoints	5	33.6×	5e-06

GO biological processes:

GO term	Partners	Fold	FDR
regulation of mitotic cell cycle	5	46.3×	5e-06
G1/S transition of mitotic cell cycle	5	38.6×	9e-06
cell division	9	16.0×	4e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	5
Uncertain significance	246
Likely benign	189
Benign	47

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1173055	NM_030928.4(CDT1):c.1078_1080del (p.Ala360del)	Pathogenic
1173056	NM_030928.4(CDT1):c.1276-24A>G	Pathogenic
1972396	NM_030928.4(CDT1):c.16del (p.Val6fs)	Pathogenic
2019767	NM_030928.4(CDT1):c.1338del (p.Gln446fs)	Pathogenic
2076232	NM_030928.4(CDT1):c.880C>T (p.Arg294Ter)	Pathogenic
2137860	NM_030928.4(CDT1):c.1560C>A (p.Tyr520Ter)	Pathogenic
2503832	NM_030928.4(CDT1):c.166_167delinsA (p.Ala56fs)	Pathogenic
2910406	NM_030928.4(CDT1):c.1279C>T (p.Arg427Ter)	Pathogenic
3020976	NM_030928.4(CDT1):c.898C>T (p.Gln300Ter)	Pathogenic
30499	NM_030928.4(CDT1):c.1560C>G (p.Tyr520Ter)	Pathogenic
30500	NM_030928.4(CDT1):c.351G>C (p.Gln117His)	Pathogenic
30501	NM_030928.4(CDT1):c.196G>A (p.Ala66Thr)	Pathogenic
3621587	NM_030928.4(CDT1):c.853C>T (p.Gln285Ter)	Pathogenic
3653953	NM_030928.4(CDT1):c.1405dup (p.Arg469fs)	Pathogenic
3724962	NM_030928.4(CDT1):c.1161_1170dup (p.Ser391fs)	Pathogenic
4693314	NM_030928.4(CDT1):c.55dup (p.Arg19fs)	Pathogenic
4704831	NM_030928.4(CDT1):c.74_83del (p.Leu25fs)	Pathogenic
4727080	NM_030928.4(CDT1):c.1505_1509dup (p.Glu504fs)	Pathogenic
4738120	NM_030928.4(CDT1):c.1394_1395del (p.Phe465fs)	Pathogenic
1324040	NM_030928.4(CDT1):c.802C>T (p.Gln268Ter)	Likely pathogenic
2070672	NM_030928.4(CDT1):c.832+2T>G	Likely pathogenic
2431870	NM_030928.4(CDT1):c.652A>T (p.Lys218Ter)	Likely pathogenic
3573508	NM_030928.4(CDT1):c.1337_1338delinsGCTTAGAA (p.Gln446delinsArgLeuGlu)	Likely pathogenic
4849302	NM_030928.4(CDT1):c.162_163insTCCC (p.Ala55fs)	Likely pathogenic

SpliceAI

1389 predictions. Top by Δscore:

Variant	Effect	Δscore
16:88804060:GTGAG:G	donor_loss	1.0000
16:88804748:T:A	acceptor_gain	1.0000
16:88805434:T:TA	acceptor_gain	1.0000
16:88805437:CA:C	acceptor_loss	1.0000
16:88805438:A:AG	acceptor_gain	1.0000
16:88805438:AGT:A	acceptor_gain	1.0000
16:88805438:AGTG:A	acceptor_gain	1.0000
16:88805439:G:GT	acceptor_gain	1.0000
16:88805439:GT:G	acceptor_gain	1.0000
16:88805439:GTG:G	acceptor_gain	1.0000
16:88805439:GTGG:G	acceptor_gain	1.0000
16:88805439:GTGGC:G	acceptor_gain	1.0000
16:88805634:GTAG:G	donor_gain	1.0000
16:88805635:TAG:T	donor_gain	1.0000
16:88805638:G:GG	donor_gain	1.0000
16:88805722:A:AG	acceptor_gain	1.0000
16:88805722:AG:A	acceptor_gain	1.0000
16:88805722:AGGC:A	acceptor_gain	1.0000
16:88805723:G:A	acceptor_loss	1.0000
16:88805723:G:GA	acceptor_gain	1.0000
16:88805723:GG:G	acceptor_gain	1.0000
16:88805723:GGC:G	acceptor_gain	1.0000
16:88805723:GGCG:G	acceptor_gain	1.0000
16:88805723:GGCGT:G	acceptor_gain	1.0000
16:88805826:G:GT	donor_gain	1.0000
16:88805865:GCAGG:G	donor_gain	1.0000
16:88805867:AGG:A	donor_gain	1.0000
16:88805868:GG:G	donor_gain	1.0000
16:88805868:GGG:G	donor_gain	1.0000
16:88805869:GG:G	donor_gain	1.0000

AlphaMissense

3503 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:88806543:T:A	W331R	0.994
16:88806543:T:C	W331R	0.994
16:88805540:T:C	F197L	0.992
16:88805542:C:A	F197L	0.992
16:88805542:C:G	F197L	0.992
16:88806555:T:C	F335L	0.991
16:88806557:C:A	F335L	0.991
16:88806557:C:G	F335L	0.991
16:88806545:G:C	W331C	0.989
16:88806545:G:T	W331C	0.989
16:88805607:T:A	V219D	0.986
16:88805619:T:A	V223D	0.985
16:88806556:T:C	F335S	0.985
16:88807398:T:C	F465L	0.985
16:88807400:T:A	F465L	0.985
16:88807400:T:G	F465L	0.985
16:88805753:T:C	I239T	0.984
16:88805552:G:C	D201H	0.983
16:88805776:T:G	Y247D	0.982
16:88806081:T:C	F298S	0.981
16:88808162:T:A	W509R	0.981
16:88808162:T:C	W509R	0.981
16:88808199:T:A	V521D	0.981
16:88805728:T:C	F231L	0.980
16:88805729:T:C	F231S	0.980
16:88805730:T:A	F231L	0.980
16:88805730:T:G	F231L	0.980
16:88805744:T:A	V236D	0.978
16:88805580:G:C	R210P	0.977
16:88805849:T:A	I271N	0.977

dbSNP variants (sampled 300 via entrez): RS1000127036 (16:88802514 A>C), RS1000187287 (16:88802007 C>T), RS1000519995 (16:88802281 A>G), RS1000923703 (16:88805664 T>A), RS1000986698 (16:88805070 C>T), RS1001019217 (16:88805229 G>T), RS1001198181 (16:88806308 G>A), RS1001321963 (16:88808503 T>C,G), RS1001363800 (16:88802307 C>A), RS1001413887 (16:88808832 T>C), RS1001827856 (16:88802632 T>C), RS1001943980 (16:88808546 G>A), RS1002304996 (16:88802821 G>A,C,T), RS1002519421 (16:88803620 C>A,G,T), RS1002524949 (16:88808723 G>A,C)

Disease associations

OMIM: gene MIM:605525 | disease phenotypes: MIM:613804, MIM:614723, MIM:224690

GenCC curated gene-disease

Disease	Classification	Inheritance
Meier-Gorlin syndrome 4	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 4	Definitive	AR

Mondo (3): Meier-Gorlin syndrome 4 (MONDO:0013431), adenine phosphoribosyltransferase deficiency (MONDO:0013869), Meier-Gorlin syndrome (MONDO:0016817)

Orphanet (2): Ear-patella-short stature syndrome (Orphanet:2554), Adenine phosphoribosyltransferase deficiency (Orphanet:976)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000039	Epispadias
HP:0000047	Hypospadias
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:0000179	Thick lower lip vermilion
HP:0000193	Bifid uvula
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000327	Hypoplasia of the maxilla
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:0000413	Atresia of the external auditory canal
HP:0000772	Abnormal rib morphology
HP:0000895	Lateral clavicle hook
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001328	Specific learning disability
HP:0001363	Craniosynostosis
HP:0001382	Joint hypermobility
HP:0001508	Failure to thrive
HP:0001510	Growth delay

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000582_1	Mean corpuscular hemoglobin concentration	4.000000e-13
GCST003479_9	Hair color	1.000000e-07
GCST004007_3	Mean corpuscular hemoglobin concentration	2.000000e-09
GCST005992_21	Mean corpuscular hemoglobin concentration	7.000000e-56
GCST006001_15	Hemoglobin A1c levels	1.000000e-12
GCST006011_46	Mean corpuscular volume	2.000000e-19
GCST007953_12	Glycated hemoglobin levels	6.000000e-06
GCST007954_32	Glycated hemoglobin levels	2.000000e-28

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004541	HbA1c measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C538228	Adenine phosphoribosyltransferase deficiency (supp.)
C538012	Meier-Gorlin syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	6
bisphenol A	affects expression, decreases expression, increases expression	3
Benzo(a)pyrene	decreases expression, increases expression, increases methylation	3
Estradiol	increases expression	3
Tretinoin	decreases expression	3
Cyclosporine	affects expression, decreases expression	3
chromium hexavalent ion	increases abundance, affects cotreatment, decreases expression, decreases phosphorylation	2
Cannabidiol	decreases expression	2
Carbamazepine	affects expression	2
Cisplatin	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Valproic Acid	decreases expression, increases methylation	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation	1
lasiocarpine	increases expression	1
propionaldehyde	decreases expression	1
androstane-3,17-dione	increases expression	1
geraniol	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects response to substance, affects expression	1
afimoxifene	decreases reaction, increases expression	1
zinc chromate	decreases expression, increases abundance	1
potassium chromate(VI)	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
nickel sulfate	increases expression	1
beta-methylcholine	affects expression	1
phenethyl isothiocyanate	decreases expression	1

Cellosaurus cell lines

13 cell lines: 6 cancer cell line, 4 spontaneously immortalized cell line, 2 conditionally immortalized cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A1TU	EndoC-betaH2-OFP-GFZ	Conditionally immortalized cell line	Sex unspecified
CVCL_A1TV	EndoC-betaH21-PGF2AOF	Conditionally immortalized cell line	Sex unspecified
CVCL_A7AU	HeLa/Fucci(CA)5	Cancer cell line	Female
CVCL_A7AV	HeLa/Fucci(SA)5	Cancer cell line	Female
CVCL_E069	NMuMG/Fucci	Spontaneously immortalized cell line	Female
CVCL_E070	HeLa/Fucci	Cancer cell line	Female
CVCL_E071	COS/Fucci	Transformed cell line	Male
CVCL_E3DA	Rat-1/T7-Cdt1 Cy CB4	Spontaneously immortalized cell line	Male
CVCL_E3DB	Rat-1/T7-Cdt1 WB4	Spontaneously immortalized cell line	Male
CVCL_U135	NMuMG/Fucci2	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02752633	PHASE4	COMPLETED	Effect of Allopurinol and Febuxostat on Urinary 2,8-Dihydroxyadenine Excretion
NCT04569149	Not specified	RECRUITING	Primordial Dwarfism Registry
NCT00588562	Not specified	RECRUITING	Rare Kidney Stone Consortium Patient Registry
NCT02026388	Not specified	RECRUITING	Rare Kidney Stone Consortium Biobank
NCT02780297	Not specified	RECRUITING	Prospective Research Rare Kidney Stones (ProRKS)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases