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CDT1 (chromatin licensing and DNA replication factor 1)

Written2009-11Rekha Deka, Ranjan Tamuli
Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati-781 039, Assam, India

(Note : for Links provided by Atlas : click)

Identity

Other aliasDUP
RIS2
LocusID (NCBI) 81620
Atlas_Id 44175
Location 16q24.3  [Link to chromosome band 16q24]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
Note CDT1 gene is present in the contig NT-010542.14 of GenBank, 430803-436282.

DNA/RNA

 
Description DNA size 5.48 kb; mRNA size 2674 bp; 10 exons.

Protein

 
Description 546 amino acids; 60433 Da.
CDT1 contains cyclin binding motif 68-70 (3), and region for geminin interaction 150-190 (41). Cyclin-binding motif is the target for phosphorylation by cyclin A-dependent kinases, which results in the binding of Cdt1 to the F-box protein Skp2 and subsequent degradation. Interaction with geminin, a small regulatory protein active during S, G2, and M phases of the cell cycle, protects CDT1 from ubiquitin mediated degradation. Six natural variants, A135V (VAR-029163), R172C (VAR-029164), R234C (VAR-054504), T262A (VAR-054505), E456A (VAR-029165), and A537V (VAR-024408) have been reported.
Isoforms : There are three different isoforms, aApr07 (complete), bApr07 (partial), and cApr07 (COOH complete); all three isoforms putatively encode good proteins.
Post translational modifications : Phosphorylation occurs at position Thr29, Ser31, Ser318, Ser372, and Ser394; however, phosphorylation does not affect binding to geminin.
Expression Widely expressed, highly expressed in liver, thymus, and predominantly expressed in uterus and cervix of female reproductive system.
Localisation Nucleus.
Function The CDT1 protein is required for the formation of the pre-replicative complexes. CDT1 cooperates with CDC6 to promote loading of the mini-chromosome maintenance complex (MCM2-7) onto chromatin to form pre-replication complex necessary for the initiation of DNA replication. Moreover, CDT1 associates with the CDC7 kinase and recruits CDC45 to chromatin during S phase. Chromatin-bound CDT1 is first stabilized and subsequently displaced by CDC7 activity, which ensures timely execution of DNA replication. CDT1 is also a potential oncogene; overexpression of CDT1 promotes rereplication and generates a DNA damage senescence and response that activates the antitumor barriers of senescence and apoptosis.
Regulation : CDT1 is regulated either by cell cycle dependent proteolysis during S and G2 phase or by geminin. Proteolysis of CDT1 during S and G2 phases is dependent on the CDK2 -cyclin A mediated phosphorylation of CDT1 and subsequent proteolysis by SCF-Skp2 complex. CDT1 activity is also inhibited by the tight binding of geminin that blocks the ability of CDT1 to load MCM2-7 onto DNA.
Homology The percent identity below represents identity of CDT1 over an aligned region in UniGene.
-Mus musculus : 82 % (percent identity)
-Bos taurus : 76.2 %
-Canis familiaris : 74.54 %
-Rattus norvegicus : 74.49 %
-Xenopus laevis : 62.5 %
-Danio rerio : 60 %.

Mutations

Note The RRL --->AAA mutation in the cyclin binding motif abolishes the binding of Cyclin A-dependent protein kinases with CDT1.

Implicated in

Note
  
Entity Lung carcinoma
Note In a subset of non-small-cell lung carcinomas (NSCLCs), CDT1 is significantly overexpressed that is positively correlated with CDC6 levels. Overexpression of CDT1-CDC6 in concert with p53-mutation is associated with higher tumor growth values and frequent aneuploidy compared with tumor bearing intact p53. These suggest a synergistic effect between CDT1-CDC6 overexpression and mutant-p53 over tumor growth and chromosomal instability in non-small-cell lung carcinomas.
  
  
Entity Colon cancer
Note CDT1 is highly expressed in human neoplastics lesions of the colon; however, its cell cycle phase specific expression profile appears to be preserved during human carcinogenesis. Overexpression of CDT1 results in rereplication, a form of endogenous DNA damage.
  
  
Entity Chromosomal damage
Note Overexpression of CDT1 induces chromosomal damage and activation of ATM-Chk2 without rereplication, resulting in chromosomal instability in normal human foreskin fibroblasts (HFF2) immortalized by telomerase. Deregulated CDT1 overexpression causes chronic chromosomal damage and instability that can eventually results in carcinogenesis. CDT1 is also highly expressed in cancer cells CaSki, HeLa, LNcap, MCF7, MDAMB231, and Saos. Overexpression of CDT1 may be at least partly due to increased transcription or increased gene copy number and CDT1 protein levels are much less affected by contact inhibition.
  

Bibliography

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 Jan 30;284(5):3028-36. Epub 2008 Dec 3.
PMID 19054765
 
Expression of the licensing factors, Cdt1 and Geminin, in human colon cancer.
Bravou V, Nishitani H, Song SY, Taraviras S, Varakis J.
Int J Oncol. 2005 Dec;27(6):1511-8.
PMID 16273206.
 
The regulated association of Cdt1 with minichromosome maintenance proteins and Cdc6 in mammalian cells.
Cook JG, Chasse DA, Nevins JR.
J Biol Chem. 2004 Mar 5;279(10):9625-33. Epub 2003 Dec 11.
PMID 14672932
 
Low pH medium induces calcium dependent release of CGRP from sensory nerves of guinea-pig dural venous sinuses.
Fanciullacci M, Tramontana M, Del Bianco E, Alessandri M, Geppetti P.
Life Sci. 1991;49(8):PL27-30.
PMID 1865750
 
Cdt1 and Cdc6 are destabilized by rereplication-induced DNA damage.
Hall JR, Lee HO, Bunker BD, Dorn ES, Rogers GC, Duronio RJ, Cook JG.
J Biol Chem. 2008 Sep 12;283(37):25356-63. Epub 2008 Jul 10.
PMID 18617514
 
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 Feb 17;281(7):3753-6. Epub 2006 Jan 3.
PMID 16407242
 
Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas: synergistic effect with mutant p53 on tumor growth and chromosomal instability--evidence of E2F-1 transcriptional control over hCdt1.
Karakaidos P, Taraviras S, Vassiliou LV, Zacharatos P, Kastrinakis NG, Kougiou D, Kouloukoussa M, Nishitani H, Papavassiliou AG, Lygerou Z, Gorgoulis VG.
Am J Pathol. 2004 Oct;165(4):1351-65.
PMID 15466399
 
Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior.
Liontos M, Koutsami M, Sideridou M, Evangelou K, Kletsas D, Levy B, Kotsinas A, Nahum O, Zoumpourlis V, Kouloukoussa M, Lygerou Z, Taraviras S, Kittas C, Bartkova J, Papavassiliou AG, Bartek J, Halazonetis TD, Gorgoulis VG.
Cancer Res. 2007 Nov 15;67(22):10899-909.
PMID 18006835
 
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 May 7;279(19):19691-7. Epub 2004 Mar 1.
PMID 14993212
 
Degradation of Cdt1 during S phase is Skp2-independent and is required for efficient progression of mammalian cells through S phase.
Takeda DY, Parvin JD, Dutta A.
J Biol Chem. 2005 Jun 17;280(24):23416-23. Epub 2005 Apr 25.
PMID 15855168.
 
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 Aug 1;119(Pt 15):3128-40. Epub 2006 Jul 11.
PMID 16835273.
 
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 Aug;271(16):3368-78.
PMID 15291814
 
The destruction box of human Geminin is critical for proliferation and tumor growth in human colon cancer cells.
Yoshida K, Oyaizu N, Dutta A, Inoue I.
Oncogene. 2004 Jan 8;23(1):58-70.
PMID 14712211
 

Citation

This paper should be referenced as such :
Deka, R ; Tamuli, R
CDT1 (chromatin licensing, DNA replication factor 1)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(9):812-814.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CDT1ID44175ch16q24.html


External links

Nomenclature
Cards
AtlasCDT1ID44175ch16q24.txt
Aliases
Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)81620
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
Miscellaneous
canSAR (ICR) (select the gene name)
Probes
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