Download Gene Section CDT1 (chromatin licensing and DNA replication factor 1)

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Gene Section
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CDT1 (chromatin licensing and DNA replication
factor 1)
Rekha Deka, Ranjan Tamuli
Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati-781 039, Assam, India
(RD, RT)
Published in Atlas Database: November 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/CDT1ID44175ch16q24.html
DOI: 10.4267/2042/44838
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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 (VAR054504), T262A (VAR-054505), E456A (VAR029165), 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.
Identity
Other names: DUP; RIS2
HGNC (Hugo): CDT1
Location: 16q24.3
Note: CDT1 gene is present in the contig NT010542.14 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).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9)
812
CDT1 (chromatin licensing and DNA replication factor 1)
Deka R, Tamuli R
Expression
Implicated in
Widely expressed, highly expressed in liver, thymus,
and predominantly expressed in uterus and cervix of
female reproductive system.
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 nonsmall-cell lung carcinomas.
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.
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.
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.
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%.
References
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Mutations
Note
The RRL --->AAA mutation in the cyclin binding
motif abolishes the binding of Cyclin A-dependent
protein kinases with CDT1.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9)
Ballabeni A, Melixetian M, Zamponi R, Masiero L, Marinoni F,
Helin K. Human geminin promotes pre-RC formation and DNA
replication by stabilizing CDT1 in mitosis. EMBO J. 2004 Aug
4;23(15):3122-32
813
CDT1 (chromatin licensing and DNA replication factor 1)
Deka R, Tamuli R
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This article should be referenced as such:
Deka R, Tamuli R. CDT1 (chromatin licensing and DNA
replication factor 1). Atlas Genet Cytogenet Oncol Haematol.
2010; 14(9):812-814.
Takeda DY, Parvin JD, Dutta A.. Degradation of Cdt1 during S
phase is Skp2-independent and is required for efficient
progression of mammalian cells through S phase. J Biol Chem.
2005 Jun 17;280(24):23416-23. Epub 2005 Apr 25.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9)
814