Details for: CDT1

Gene ID: 81620

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: CDT1

Ensembl ID: ENSG00000167513

Description: chromatin licensing and DNA replication factor 1

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • common myeloid progenitor CL0000049
    CSI 6.58
    rCSI 5.32%
    PRS 95.62
  • pro-B cell CL0000826
    CSI 5.79
    rCSI 4.79%
    PRS 95.6
  • plasmablast CL0000980
    CSI 4.73
    rCSI 3.72%
    PRS 95.75
  • transit amplifying cell of colon CL0009011
    CSI 4.56
    rCSI 5.35%
    PRS 94.96
  • epithelial cell CL0000066
    CSI 3.95
    rCSI 6.06%
    PRS 84.99
  • primitive red blood cell CL0002355
    CSI 3.61
    rCSI 19.49%
    PRS 95.29
  • neural crest cell CL0011012
    CSI 3.39
    rCSI 2.68%
    PRS 90.66
  • early lymphoid progenitor CL0000936
    CSI 3.35
    rCSI 2.94%
    PRS 96.84
  • radial glial cell CL0000681
    CSI 2.95
    rCSI 4.09%
    PRS 93.59
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 2.82
    rCSI 2.54%
    PRS 94.13
  • large pre-B-II cell CL0000957
    CSI 2.82
    rCSI 8.04%
    PRS 94
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 2.72
    rCSI 3.14%
    PRS 89.25
  • intestinal epithelial cell CL0002563
    CSI 2.66
    rCSI 2.78%
    PRS 93.11
  • fraction A pre-pro B cell CL0002045
    CSI 2.57
    rCSI 2.94%
    PRS 96.69
  • mesenchymal cell CL0008019
    CSI 2.57
    rCSI 6.52%
    PRS 91.96
  • multi-ciliated epithelial cell CL0005012
    CSI 2.5
    rCSI 2.49%
    PRS 90.66
  • granulocyte monocyte progenitor cell CL0000557
    CSI 2.48
    rCSI 2.15%
    PRS 95.95
  • stem cell CL0000034
    CSI 2.42
    rCSI 2.34%
    PRS 92.57
  • placental villous trophoblast CL2000060
    CSI 2.4
    rCSI 3.71%
    PRS 93.47
  • extravillous trophoblast CL0008036
    CSI 2.33
    rCSI 2.88%
    PRS 93.44
  • mesodermal cell CL0000222
    CSI 2.21
    rCSI 2.66%
    PRS 94.45
  • promyelocyte CL0000836
    CSI 2.13
    rCSI 3.07%
    PRS 95.75
  • common dendritic progenitor CL0001029
    CSI 2.11
    rCSI 2.65%
    PRS 97.42
  • neuroblast (sensu Vertebrata) CL0000031
    CSI 2.03
    rCSI 2.6%
    PRS 92.15
  • promonocyte CL0000559
    CSI 1.52
    rCSI 2.61%
    PRS 95.73
  • germinal center B cell CL0000844
    CSI 1.04
    rCSI 3.09%
    PRS 96.44
  • erythroblast CL0000765
    CSI 1.02
    rCSI 2.7%
    PRS 94.83
  • myeloid lineage restricted progenitor cell CL0000839
    CSI 0.9
    rCSI 4.67%
    PRS 98.67
  • deuterosomal cell CL4033044
    CSI 0.84
    rCSI 2.85%
    PRS 89.79
  • erythroid progenitor cell CL0000038
    CSI 0.61
    rCSI 3.48%
    PRS 95.82
  • eosinophil CL0000771
    CSI 0.61
    rCSI 3.98%
    PRS 98.24
  • megakaryocyte progenitor cell CL0000553
    CSI 0.4
    rCSI 7.3%
    PRS 98.91
  • pluripotent stem cell CL0002248
    CSI 0.22
    rCSI 6.59%
    PRS 97.1

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
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    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Chromatin licensing and DNA replication factor 1, encoded by the [CDT1](/details-gene/81620) gene, is a fundamental protein essential for the initiation of DNA replication. As a key component of the pre-replicative complex (pre-RC), [CDT1](/details-gene/81620) ensures that DNA is replicated only once per cell cycle by loading the minichromosome maintenance (MCM) complex onto chromatin at origins of replication during the G1 phase. Its activity is tightly regulated through interactions with proteins like geminin and via proteasomal degradation to prevent DNA re-replication and maintain genomic stability ([Link](https://doi.org/10.1126/science.290.5500.2309)). **Overall**, expression data reveals that [CDT1](/details-gene/81620) has the highest significance in highly proliferative cell populations, including hematopoietic progenitors such as the [common myeloid progenitor](/details-cell/CL0000049) and [pro-B cell](/details-cell/CL0000826), as well as rapidly dividing epithelial precursors like the [transit amplifying cell of colon](/details-cell/CL0009011), underscoring its central role in tissue development and renewal. ## Cellular Roles and Expression Landscape The expression profile of [CDT1](/details-gene/81620) is strongly indicative of its function as a master regulator of cell cycle entry and proliferation. The gene's highest significance is observed in a diverse array of progenitor and precursor cells across multiple lineages. Within the hematopoietic system, [CDT1](/details-gene/81620) is a prominent marker for [common myeloid progenitor](/details-cell/CL0000049) cells (CSI: 6.58), [pro-B cell](/details-cell/CL0000826)s (CSI: 5.79), [plasmablast](/details-cell/CL0000980)s (CSI: 4.73), and [early lymphoid progenitor](/details-cell/CL0000936)s (CSI: 3.35). This pattern highlights its indispensable role during the rapid cell divisions required for the development and expansion of both myeloid and lymphoid lineages. Beyond hematopoiesis, [CDT1](/details-gene/81620) is also highly significant in other actively dividing cell populations. These include [transit amplifying cell of colon](/details-cell/CL0009011) (CSI: 4.56) and general [epithelial cell](/details-cell/CL0000066)s (CSI: 3.95), which are responsible for the constant renewal of the intestinal lining. Furthermore, its significance in developmental contexts is demonstrated by its expression in [neural crest cell](/details-cell/CL0011012)s and [radial glial cell](/details-cell/CL0000681)s. The common feature uniting these disparate cell types is their high mitotic activity, consistent with the gene's primary function in licensing DNA for replication. The absence of terminally differentiated, post-mitotic cells in the top expression list further suggests that [CDT1](/details-gene/81620) expression is tightly restricted to cells actively participating in the cell cycle. ## Pathways and Molecular Function The molecular functions and pathway associations of [CDT1](/details-gene/81620) are centered on the precise control of DNA replication and cell cycle progression. Gene Ontology (GO) annotations confirm its role in processes such as '[Dna replication preinitiation complex assembly](https://www.ebi.ac.uk/QuickGO/term/GO:0071163)', '[Positive regulation of dna replication](https://www.ebi.ac.uk/QuickGO/term/GO:0045740)', and '[Mitotic cell cycle](https://www.ebi.ac.uk/QuickGO/term/GO:0000278)'. Its molecular function is defined by its ability to engage in '[Chromatin binding](https://www.ebi.ac.uk/QuickGO/term/GO:0003682)' and '[Dna polymerase binding](https://www.ebi.ac.uk/QuickGO/term/GO:0070182)', localizing it to the '[Nucleus](https://www.ebi.ac.uk/QuickGO/term/GO:0005634)' and specifically to the '[Kinetochore](https://www.ebi.ac.uk/QuickGO/term/GO:0000776)'. Reactome pathway analysis provides a granular view of its role, placing [CDT1](/details-gene/81620) at the heart of the '[G1/s transition](https://reactome.org/content/detail/R-HSA-69206)' ([Link](https://reactome.org/content/detail/R-HSA-69206)). It is a critical factor in the '[Assembly of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68867)' and the subsequent '[Activation of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68962)', which are prerequisite steps for initiating the '[S phase](https://reactome.org/content/detail/R-HSA-69242)'. Research has established that its function is tightly controlled by phosphorylation via cyclin-dependent kinases and by its stoichiometric inhibitor, geminin, which prevents re-licensing of replicated DNA ([Link](https://doi.org/10.1074/jbc.m313175200), [Link](https://doi.org/10.1126/science.290.5500.2309)). Furthermore, its proteolysis is regulated in response to DNA damage, involving complexes such as CUL4/DDB1, providing a checkpoint to halt replication in the presence of genomic stress ([Link](https://doi.org/10.4161/cc.5.15.3149)). ## Research Directions The central role of [CDT1](/details-gene/81620) in DNA replication makes its dysregulation a likely contributor to diseases characterized by uncontrolled cell proliferation, such as cancer. Its high expression in various progenitor cells presents compelling avenues for investigation into both normal development and pathology. **Proposed Hypotheses:** 1. Misregulation or overexpression of [CDT1](/details-gene/81620) in hematopoietic progenitors, such as the [common myeloid progenitor](/details-cell/CL0000049), may promote leukemogenesis by lowering the threshold for cell cycle entry and increasing the risk of genomic instability through DNA re-replication events. 2. Given its high significance in the [transit amplifying cell of colon](/details-cell/CL0009011), aberrant stabilization or increased expression of [CDT1](/details-gene/81620) could be an early initiating event in the adenoma-carcinoma sequence of colorectal cancer, driving the clonal expansion of pre-cancerous lesions. **Experimental Approach:** To test the first hypothesis regarding leukemogenesis, a conditional knockout mouse model could be generated where [CDT1](/details-gene/81620) is specifically deleted in hematopoietic stem and progenitor cells (HSPCs). Conversely, an inducible overexpression model could also be created. Following induction, bone marrow cells would be analyzed for changes in cell cycle distribution (via BrdU/EdU incorporation assays), differentiation capacity (through colony-forming unit assays and flow cytometry), and markers of replication stress and DNA damage (e.g., γ-H2AX foci). Serial bone marrow transplantation experiments could then determine if altered [CDT1](/details-gene/81620) levels are sufficient to initiate or accelerate myeloid malignancies in vivo. **Therapeutic Potential:** As a non-enzymatic core component of the replication machinery, [CDT1](/details-gene/81620) presents a challenging but attractive therapeutic target. Direct **inhibition** would be the desired strategy. While broad suppression of [CDT1](/details-gene/81620) would likely be toxic to all proliferating tissues, developing molecules that disrupt its specific protein-protein interactions—such as its binding to the MCM complex or its coactivator HBO1 ([Link](https://doi.org/10.1101/gad.1674108))—could offer a more targeted approach. Cancers exhibiting high levels of replication stress might be disproportionately sensitive to such inhibitors, providing a potential therapeutic window. Such a strategy could be particularly effective in hematological malignancies or solid tumors that are highly dependent on rapid cell division for their growth and survival.

Genular Protein ID: 2992123391

Symbol: CDT1_HUMAN

Name: DNA replication factor Cdt1

UniProtKB Accession Codes:

Q9H211 Q86XX9 Q96CJ5 Q96GK5 Q96H67 Q96HE6 Q9BWM0

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 2 CORUM 1 CTD 1 ChiTaRS 1 ComplexPortal 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 10 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 20 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 MoonProt 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 3 PDBsum 3 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 5 RefSeq 1 SASBDB 1 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 11125146

Title: Inhibition of eukaryotic DNA replication by geminin binding to Cdt1.

PubMed ID: 11125146

DOI: 10.1126/science.290.5500.2309

PubMed ID: 10766248

Title: The Cdt1 protein is required to license DNA for replication in fission yeast.

PubMed ID: 10766248

DOI: 10.1038/35007110

PubMed ID: 15616553

Title: The sequence and analysis of duplication-rich human chromosome 16.

PubMed ID: 15616553

DOI: 10.1038/nature03187

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 14990995

Title: Regulation of Geminin and Cdt1 expression by E2F transcription factors.

PubMed ID: 14990995

DOI: 10.1038/sj.onc.1207488

PubMed ID: 18832067

Title: HBO1 histone acetylase is a coactivator of the replication licensing factor Cdt1.

PubMed ID: 18832067

DOI: 10.1101/gad.1674108

PubMed ID: 18669648

Title: A quantitative atlas of mitotic phosphorylation.

PubMed ID: 18669648

DOI: 10.1073/pnas.0805139105

PubMed ID: 19690332

Title: Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.

PubMed ID: 19690332

DOI: 10.1126/scisignal.2000007

PubMed ID: 21856198

Title: JNK1 phosphorylation of Cdt1 inhibits recruitment of HBO1 histone acetylase and blocks replication licensing in response to stress.

PubMed ID: 21856198

DOI: 10.1016/j.molcel.2011.06.021

PubMed ID: 15257290

Title: Human geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis.

PubMed ID: 15257290

DOI: 10.1038/sj.emboj.7600314

PubMed ID: 14672932

Title: The regulated association of Cdt1 with minichromosome maintenance proteins and Cdc6 in mammalian cells.

PubMed ID: 14672932

DOI: 10.1074/jbc.m311933200

PubMed ID: 14993212

Title: Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding.

PubMed ID: 14993212

DOI: 10.1074/jbc.m313175200

PubMed ID: 16861906

Title: L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and regulates CDT1 proteolysis in response to DNA damage.

PubMed ID: 16861906

DOI: 10.4161/cc.5.15.3149

PubMed ID: 17085480

Title: DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint.

PubMed ID: 17085480

DOI: 10.1101/gad.1482106

PubMed ID: 16949367

Title: A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1.

PubMed ID: 16949367

DOI: 10.1016/j.molcel.2006.08.010

PubMed ID: 21543332

Title: Idas, a novel phylogenetically conserved geminin-related protein, binds to geminin and is required for cell cycle progression.

PubMed ID: 21543332

DOI: 10.1074/jbc.m110.207688

PubMed ID: 22645314

Title: Dynamic association of ORCA with prereplicative complex components regulates DNA replication initiation.

PubMed ID: 22645314

DOI: 10.1128/mcb.00362-12

PubMed ID: 22581055

Title: Recruitment of the human Cdt1 replication licensing protein by the loop domain of Hec1 is required for stable kinetochore-microtubule attachment.

PubMed ID: 22581055

DOI: 10.1038/ncb2489

PubMed ID: 23186163

Title: Toward a comprehensive characterization of a human cancer cell phosphoproteome.

PubMed ID: 23186163

DOI: 10.1021/pr300630k

PubMed ID: 25990725

Title: Cdt1-binding protein GRWD1 is a novel histone-binding protein that facilitates MCM loading through its influence on chromatin architecture.

PubMed ID: 25990725

DOI: 10.1093/nar/gkv509

PubMed ID: 27296872

Title: USP37 deubiquitinates Cdt1 and contributes to regulate DNA replication.

PubMed ID: 27296872

DOI: 10.1016/j.molonc.2016.05.008

PubMed ID: 26842564

Title: Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression.

PubMed ID: 26842564

DOI: 10.1038/ncomms10612

PubMed ID: 21358632

Title: Mutations in the pre-replication complex cause Meier-Gorlin syndrome.

PubMed ID: 21358632

DOI: 10.1038/ng.775

PubMed ID: 21358631

Title: Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome.

PubMed ID: 21358631

DOI: 10.1038/ng.777

Sequence Information:

  • Length: 546
  • Mass: 60390
  • Checksum: 8179D0330C135FB7
  • Sequence:
    • MEQRRVTDFF ARRRPGPPRI APPKLACRTP SPARPALRAP ASATSGSRKR ARPPAAPGRD 
QARPPARRRL RLSVDEVSSP STPEAPDIPA CPSPGQKIKK STPAAGQPPH LTSAQDQDTI 
SELASCLQRA RELGARVRAL KASAQDAGES CTPEAEGRPE EPCGEKAPAY QRFHALAQPG 
LPGLVLPYKY QVLAEMFRSM DTIVGMLHNR SETPTFAKVQ RGVQDMMRRR FEECNVGQIK 
TVYPASYRFR QERSVPTFKD GTRRSDYQLT IEPLLEQEAD GAAPQLTASR LLQRRQIFSQ 
KLVEHVKEHH KAFLASLSPA MVVPEDQLTR WHPRFNVDEV PDIEPAALPQ PPATEKLTTA 
QEVLARARNL ISPRMEKALS QLALRSAAPS SPGSPRPALP ATPPATPPAA SPSALKGVSQ 
DLLERIRAKE AQKQLAQMTR CPEQEQRLQR LERLPELARV LRSVFVSERK PALSMEVACA 
RMVGSCCTIM SPGEMEKHLL LLSELLPDWL SLHRIRTDTY VKLDKAADLA HITARLAHQT 
RAEEGL