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Gene Review

CDT1  -  chromatin licensing and DNA replication...

Homo sapiens

Synonyms: DNA replication factor Cdt1, DUP, Double parked homolog, RIS2
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Disease relevance of CDT1

  • The Cul4A gene is amplified in human breast and liver cancers, and loss-of-function of Cul4 results in the accumulation of the replication licensing factor CDT1 in Caenorhabditis elegans embryos and ultraviolet (UV)-irradiated human cells [1].
  • Constitutive expression of Cdt1 causes DNA re-replication and is associated with the development of a subset of human non-small cell-lung carcinomas [2].
  • Expression of the licensing factors, Cdt1 and Geminin, in human colon cancer [3].
  • In the latent state, the EBV genomic DNA, which exists as a closed circular plasmid, appears to behave just like host chromosomal DNA and it has been demonstrated recently that replication of OriP-containing plasmids is indeed dependent on the chromosomal initiation factors, ORC2 and Cdt1 [4].
  • Thus, our study indicates that DUP is more reproducible and more accurate than SD in identifying patients with CAD and LV dyskinesia [5].

Psychiatry related information on CDT1

  • For patients first presenting with a non-affective psychotic disorder, the duration of untreated psychosis (DUP; the time between the onset of positive psychotic symptoms and the initiation of appropriate treatment) varies widely, from a few weeks to several years [6].
  • 5. DUP 996-induced EEG-changes over time were most pronounced over temporo-occipital, temporo-frontal, parietal and frontal regions, e.g. over brain areas afflicted most by Alzheimer's disease [7].
  • It would appear that as years of chronic, refractory illness accrue, psychomotor poverty becomes more sharply delineated and dominant within the overall structure of psychopathology, and its prominence is predicted enduringly by DUP [8].
  • The specificity at the same level of alcohol consumption, markedly differed between the two methods: 92%, 76% and 90% for CDTect, AX CDT 1 and AX CDT 2, respectively [9].
  • There were significant associations between internal locus of control score and short DUP, and between external locus of control score and a positive attitude to medication as measured by the Drug Attitudes Inventory [10].

High impact information on CDT1


Chemical compound and disease context of CDT1

  • We examined the influence of exposure time to DUP 785 on its growth-inhibitory effects in L1210 murine leukemia and WiDR human adenocarcinoma cells and the effects of pyrimidine (deoxy) nucleosides on reversal of growth-inhibition [14].
  • 1. In a double-blind, placebo-controlled study the encephalotropic effects of DUP 996, a novel phenylindolinone derivative for Alzheimer's disease enhancing the release of acetylcholine in cholinergic nerve terminals in the brain only when its release is triggered, were studied with special consideration of the pharmacodynamic time-course [7].

Biological context of CDT1

  • Our study reveals an evolutionarily conserved and uncharacterized G1 checkpoint that induces CDT1 proteolysis by the CUL4-ROC1 ubiquitin E3 ligase and CSN complexes in response to DNA damage [15].
  • We show that radiation-mediated CDT1 proteolysis is independent of ATM and CHK2 and can occur in G1-phase cells [15].
  • Geminin is an unstable inhibitor of DNA replication that negatively regulates the licensing factor CDT1 and inhibits pre-replicative complex (pre-RC) formation in Xenopus egg extracts [16].
  • Human geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis [16].
  • The current concept regarding cell cycle regulation of DNA replication is that Cdt1, together with origin recognition complex and CDC6 proteins, constitutes the machinery that loads the minichromosome maintenance complex, a candidate replicative helicase, onto chromatin during the G(1) phase [17].

Anatomical context of CDT1


Associations of CDT1 with chemical compounds

  • However, threonine 29 and the Cy motif are not necessary for proteolysis of Cdt1 during S phase [22].
  • An array of glutamic acid residues on the coiled-coil domain surface interacts with positive charges in the middle of Cdt1 [23].
  • CONCLUSIONS: This is the first report of complete thyroxine-binding globulin deficiency (TBG-CDT1 and TBG-CDT2) due to TBG gene mutations in Taiwan [24].
  • Based on T-DNA activation tagging, a gene (CDT-1) was isolated which encodes a signalling molecule in the ABA transduction pathway [25].
  • In nonfailing hearts, 69 +/- 4% of binding sites were blocked by the subtype-2-specific inhibitor PD 123319 and were therefore classified as AT2; 33 +/- 5% were blocked by the subtype-1-specific inhibitor DUP 753 and thus classified as subtype 1 [26].
  • In vitro, Cdt1 can be acetylated at its N terminus by the lysine acetyltransferases KAT2B and KAT3B [27].

Physical interactions of CDT1


Enzymatic interactions of CDT1

  • Cyclin-dependent kinases phosphorylate human Cdt1 and induce its degradation [31].

Regulatory relationships of CDT1

  • L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and regulates CDT1 proteolysis in response to DNA damage [28].
  • The most important finding in these studies is that deregulated Cdt1 induces chromosomal damage and activation of the ATM-Chk2 DNA damage checkpoint pathway even in quiescent cells [32].
  • These Cdt1 activities are negatively regulated by cyclin A/Cdks, probably through modification by phosphorylation [32].
  • These findings suggest that exogenous Cdt1 induces re-replication by de-repressing endogenous Cdt1 through the titration of PCNA and cyclin [33].

Other interactions of CDT1

  • Once the origin recognition complex (ORC) binds to origins, CDC6 and CDT1 associate with ORC and promote loading of the MCM2-7 proteins onto chromatin, generating the preRC [15].
  • Phosphorylated Cdt1 is subsequently recognized by the F-box protein Skp2 and targeted for proteasomal mediated degradation [22].
  • Several mechanisms of pre-RC regulation are known, including ATP utilization, cyclin-dependent kinase levels, protein turnover, and Cdt1 binding by geminin [34].
  • Regulation of Geminin and Cdt1 expression by E2F transcription factors [35].
  • Geminin has been proposed to coordinate cell cycle and differentiation events through balanced interactions with the cell cycle regulator Cdt1 and with homeobox transcription factors and chromatin remodeling activities implicated in cell fate decisions [36].
  • We show that human CDT1 associates with the CDC7 kinase and recruits CDC45 to chromatin [37].

Analytical, diagnostic and therapeutic context of CDT1


  1. Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage. Hu, J., McCall, C.M., Ohta, T., Xiong, Y. Nat. Cell Biol. (2004) [Pubmed]
  2. An evolutionarily conserved function of proliferating cell nuclear antigen for Cdt1 degradation by the Cul4-Ddb1 ubiquitin ligase in response to DNA damage. Hu, J., Xiong, Y. J. Biol. Chem. (2006) [Pubmed]
  3. Expression of the licensing factors, Cdt1 and Geminin, in human colon cancer. Bravou, V., Nishitani, H., Song, S.Y., Taraviras, S., Varakis, J. Int. J. Oncol. (2005) [Pubmed]
  4. Latent and lytic Epstein-Barr virus replication strategies. Tsurumi, T., Fujita, M., Kudoh, A. Rev. Med. Virol. (2005) [Pubmed]
  5. Quantitation of left ventricular asynchrony on radionuclide angiography phase images. Alfano, B., Betocchi, S., Pace, L., Perrone-Filardi, P., Chiariello, M., Salvatore, M. European journal of nuclear medicine. (1990) [Pubmed]
  6. Duration of untreated psychosis predicts treatment outcome in an early psychosis program. Black, K., Peters, L., Rui, Q., Milliken, H., Whitehorn, D., Kopala, L.C. Schizophr. Res. (2001) [Pubmed]
  7. EEG brain mapping in evaluating the time-course of the central action of DUP 996--a new acetylcholine releasing drug. Saletu, B., Darragh, A., Salmon, P., Coen, R. British journal of clinical pharmacology. (1989) [Pubmed]
  8. Longitudinal assessment of psychopathological domains over late-stage schizophrenia in relation to duration of initially untreated psychosis: 3-year prospective study in a long-term inpatient population. Meagher, D.J., Quinn, J.F., Bourke, S., Linehan, S., Murphy, P., Kinsella, A., Mullaney, J., Waddington, J.L. Psychiatry research. (2004) [Pubmed]
  9. A comparison between two commercial methods for determining carbohydrate deficient transferrin (CDT). Bell, H., Tallaksen, C.C., Haug, E., Try, K. Scand. J. Clin. Lab. Invest. (1994) [Pubmed]
  10. Health beliefs link to duration of untreated psychosis and attitudes to later treatment in early psychosis. Haley, C.J., Drake, R.J., Bentall, R.P., Lewis, S.W. Social psychiatry and psychiatric epidemiology. (2003) [Pubmed]
  11. The Cdt1 protein is required to license DNA for replication in fission yeast. Nishitani, H., Lygerou, Z., Nishimoto, T., Nurse, P. Nature (2000) [Pubmed]
  12. Inhibition of eukaryotic DNA replication by geminin binding to Cdt1. Wohlschlegel, J.A., Dwyer, B.T., Dhar, S.K., Cvetic, C., Walter, J.C., Dutta, A. Science (2000) [Pubmed]
  13. DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint. Sansam, C.L., Shepard, J.L., Lai, K., Ianari, A., Danielian, P.S., Amsterdam, A., Hopkins, N., Lees, J.A. Genes Dev. (2006) [Pubmed]
  14. DUP 785 (NSC 368390): schedule-dependency of growth-inhibitory and antipyrimidine effects. Schwartsmann, G., Peters, G.J., Laurensse, E., de Waal, F.C., Loonen, A.H., Leyva, A., Pinedo, H.M. Biochem. Pharmacol. (1988) [Pubmed]
  15. Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes constitutes a new checkpoint. Higa, L.A., Mihaylov, I.S., Banks, D.P., Zheng, J., Zhang, H. Nat. Cell Biol. (2003) [Pubmed]
  16. Human geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis. Ballabeni, A., Melixetian, M., Zamponi, R., Masiero, L., Marinoni, F., Helin, K. EMBO J. (2004) [Pubmed]
  17. Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding. Sugimoto, N., Tatsumi, Y., Tsurumi, T., Matsukage, A., Kiyono, T., Nishitani, H., Fujita, M. J. Biol. Chem. (2004) [Pubmed]
  18. Regulation of CDC6, geminin, and CDT1 in human cells that undergo polyploidization. Bermejo, R., Vilaboa, N., Calés, C. Mol. Biol. Cell (2002) [Pubmed]
  19. Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis. Nishitani, H., Sugimoto, N., Roukos, V., Nakanishi, Y., Saijo, M., Obuse, C., Tsurimoto, T., Nakayama, K.I., Nakayama, K., Fujita, M., Lygerou, Z., Nishimoto, T. EMBO J. (2006) [Pubmed]
  20. Expression of geminin as a marker of cell proliferation in normal tissues and malignancies. Wohlschlegel, J.A., Kutok, J.L., Weng, A.P., Dutta, A. Am. J. Pathol. (2002) [Pubmed]
  21. Cdt1 and geminin: role during cell cycle progression and DNA damage in higher eukaryotes. Tada, S. Front. Biosci. (2007) [Pubmed]
  22. Degradation of Cdt1 during S phase is Skp2-independent and is required for efficient progression of mammalian cells through S phase. Takeda, D.Y., Parvin, J.D., Dutta, A. J. Biol. Chem. (2005) [Pubmed]
  23. A dimerized coiled-coil domain and an adjoining part of geminin interact with two sites on Cdt1 for replication inhibition. Saxena, S., Yuan, P., Dhar, S.K., Senga, T., Takeda, D., Robinson, H., Kornbluth, S., Swaminathan, K., Dutta, A. Mol. Cell (2004) [Pubmed]
  24. Two novel mutations in the gene encoding thyroxine-binding globulin (TBG) as a cause of complete TBG deficiency in Taiwan. Su, C.C., Wu, Y.C., Chiu, C.Y., Won, J.G., Jap, T.S. Clin. Endocrinol. (Oxf) (2003) [Pubmed]
  25. High level transcription of a member of a repeated gene family confers dehydration tolerance to callus tissue of Craterostigma plantagineum. Furini, A., Koncz, C., Salamini, F., Bartels, D. EMBO J. (1997) [Pubmed]
  26. Regulation, chamber localization, and subtype distribution of angiotensin II receptors in human hearts. Regitz-Zagrosek, V., Friedel, N., Heymann, A., Bauer, P., Neuss, M., Rolfs, A., Steffen, C., Hildebrandt, A., Hetzer, R., Fleck, E. Circulation (1995) [Pubmed]
  27. Acetylation/deacetylation modulates the stability of DNA replication licensing factor Cdt1. Glozak, M.A., Seto, E. J. Biol. Chem. (2009) [Pubmed]
  28. L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and regulates CDT1 proteolysis in response to DNA damage. Higa, L.A., Banks, D., Wu, M., Kobayashi, R., Sun, H., Zhang, H. Cell Cycle (2006) [Pubmed]
  29. The SCF(Skp2) ubiquitin ligase complex interacts with the human replication licensing factor Cdt1 and regulates Cdt1 degradation. Li, X., Zhao, Q., Liao, R., Sun, P., Wu, X. J. Biol. Chem. (2003) [Pubmed]
  30. The human licensing factor for DNA replication Cdt1 accumulates in G1 and is destabilized after initiation of S-phase. Nishitani, H., Taraviras, S., Lygerou, Z., Nishimoto, T. J. Biol. Chem. (2001) [Pubmed]
  31. Cyclin-dependent kinases phosphorylate human Cdt1 and induce its degradation. Liu, E., Li, X., Yan, F., Zhao, Q., Wu, X. J. Biol. Chem. (2004) [Pubmed]
  32. Deregulation of Cdt1 induces chromosomal damage without rereplication and leads to chromosomal instability. Tatsumi, Y., Sugimoto, N., Yugawa, T., Narisawa-Saito, M., Kiyono, T., Fujita, M. J. Cell. Sci. (2006) [Pubmed]
  33. Human Cdt1 lacking the evolutionarily conserved region that interacts with MCM2-7 is capable of inducing re-replication. Teer, J.K., Dutta, A. J. Biol. Chem. (2008) [Pubmed]
  34. Regulation of replication licensing by acetyltransferase Hbo1. Iizuka, M., Matsui, T., Takisawa, H., Smith, M.M. Mol. Cell. Biol. (2006) [Pubmed]
  35. Regulation of Geminin and Cdt1 expression by E2F transcription factors. Yoshida, K., Inoue, I. Oncogene (2004) [Pubmed]
  36. Geminin Cleavage during Apoptosis by Caspase-3 Alters Its Binding Ability to the SWI/SNF Subunit Brahma. Roukos, V., Iliou, M.S., Nishitani, H., Gentzel, M., Wilm, M., Taraviras, S., Lygerou, Z. J. Biol. Chem. (2007) [Pubmed]
  37. Human CDT1 associates with CDC7 and recruits CDC45 to chromatin during S phase. Ballabeni, A., Zamponi, R., Caprara, G., Melixetian, M., Bossi, S., Masiero, L., Helin, K. J. Biol. Chem. (2009) [Pubmed]
  38. The replicative regulator protein geminin on chromatin in the HeLa cell cycle. Kulartz, M., Knippers, R. J. Biol. Chem. (2004) [Pubmed]
  39. Cdt1 and geminin are down-regulated upon cell cycle exit and are over-expressed in cancer-derived cell lines. Xouri, G., Lygerou, Z., Nishitani, H., Pachnis, V., Nurse, P., Taraviras, S. Eur. J. Biochem. (2004) [Pubmed]
  40. Thrombin and human plasma kallikrein inhibition during simulated extracorporeal circulation block platelet and neutrophil activation. Wachtfogel, Y.T., Kettner, C., Hack, C.E., Nuijens, J.H., Reilly, T.M., Knabb, R.M., Kucich, U., Niewiarowski, S., Edmunds, L.H., Colman, R.W. Thromb. Haemost. (1998) [Pubmed]
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