Review on CDC6 (cell division cycle 6 homolog (S. cerevisiae)), with data on DNA, on the protein encoded, and where the gene is implicated

Gorgoulis, VG

Zachariadis, M

Atlas of Genetics and Cytogenetics in Oncology and Haematology

I-Revues

 
 
 
 
 
 
Gene Section 
Mini Review 
 
Atlas Genet Cytogenet Oncol Haematol. 2008;12(5)  362 
Atlas of Genetics and Cytogenetics 
in Oncology and Haematology                          
                         OPEN ACCESS JOURNAL AT INIST-CNRS 
CDC6 (cell division cycle 6 homolog (S. 
cerevisiae)) 
Michael Zachariadis, Vassilis G Gorgoulis 
Department of Anatomy, Faculty of Medicine, University of Athens, Athens, Greece (MZ); Department of 
Histology and Embryology, Molecular Carcinogenesis Group, Faculty of Medicine, University of Athens, 
Athens, Greece (VGG) 
Published in Atlas Database: January 2008 
Online updated version: http://AtlasGeneticsOncology.org/Genes/CDC6ID40014ch17q21.html  
DOI: 10.4267/2042/38568 
This work is licensed under a Creative Commons Attribution-Non-commercial-No-Derivative Works 2.0 France License. 
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology 
 
Identity 
Hugo: CDC6 
Other names: CDC18L; cdc6; hCDC6; HsCDC18; 
HsCDC6; p62 
Location: 17q21.3 
Local order: centrosome ---- CASC3-RAPGEFL1-
WIPF2-CDC6-RARA-TOP2A 
DNA/RNA 
Accession 
N° 
Transcript 
length (bp) Notes 
NM_001254 3053 RefSeq 
CR598029 1802 mRNA 
BC025232 2861 mRNA 
HSU77949 2653 mRNA 
AF022109 2021 mRNA 
Description 
The gene starts at 35697672 bp from pter and ends at 
35712939 bp from pter. Its size is 15267 bases and its 
orientation lie at the plus strand. 
The 5' promoter region contains putative sites for 
transcriptional control, including an initiator elem nt, a 
CHR element, two main binding sites for E2F, a 
putative Sp1 site, and a CCAAT region. No consensus 
TATA box is evident. This resembles the organization 
of other genes encoding proteins associated with the 
G1/S transition. 
Transcription 
The gene has 12 exons. The five putative transcript 
(see table below) encode the same product of 560aa. 
There are about 230 EST sequences. 
Pseudogene 
There are no known pseudogenes. 
Protein 
Description 
The CDC6 protein or p62 is composed of 560 amino 
acids with a molecular weight of 62720 Da. The central 
portion of the protein contains a conserved nucleotid  
binding/ATPase domain, which classifies it to a large 
superfamily of ATPases known as "ATPases associated 
with various cellular activities" (AAA) proteins and 
specifically to the AAA+ subfamily. The Walker-A 
motif GXXGXGK(T/S) (nucleotide binding) of the 
AAA+ domain spans aa 202-209, while the Walker-B 
motif D(D/E)XX (nucleotide hydrolysis) spans aa 284-
287. The domain contains also a leucine zipper (aa 306-
327), and a caspase dependent cleavage site 
DQL290DS. 
The N-terminal domain contains: three consensus 
phosphorylation sites at serine (S)54, S74 and S106, 
which are phosphorylated in vivo by CDK-related 
activity at the G1/S boundary; a putative conserved 
nuclear localization sequence ((S/T)PXK57R58(L/I)); 
two putative destruction boxes (D-box (aa 56-64) and
KEN box (aa 81-83)), which target CDC6 for 
proteolysis by APCCDH1 during early G1 or G0, but  
CDC6 (cell division cycle 6 homolog (S. cerevisiae)) Zachariadis M, Gorgoulis VG 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2008;12(5)  363 
not S, G2 or M; and a cyclin binding domain mapped to 
a Cy-motif (aa 93-100) that is similar to the cyclin 
binding regions in p21/WAF1/SDI1 and E2F-1. 
The C-terminal domain contains: a putative classical 
nuclear export signal (NES) between residues 462-488 
(ILVCSLMLLIRQLKI), a caspase dependent cleavage 
site SEV442DG, and a conserved winged-helix domain 
(WHD) with unknown function; it possibly mediates 
protein-protein interactions or a direct interaction with 
the DNA helix. 
Expression 
It is expressed in all proliferating cells but not in 
quiescent or differentiated cells. 
Localisation 
Even though it was believed at first that p62CDC6 was 
nuclear during G1 and cytoplasmic during S and G2, 
lately it has been found that there is an endogenous 
fraction of the protein that remains chromatin-bound 
throughout the cell cycle. 
Function 
- ATP binding 
- Chromatin binding 
- Nucleoside-triphosphatase activity 
- Nucleotide binding 
- Protein binding 
- Loading factor for MCM2-7: Cdc6/Cdc18 is recruited 
to replication origins by ORC. Once localized at 
replication origins, Cdc6 helps to recruit and load 
MCM factors onto DNA in a process that requires 
CDC6-mediated ATP hydrolysis. After loading of 
MCM2-7 on DNA, CDC6 is not necessary for origin 
firing and dissociates from the complex, through a 
phosphorylation-dependent procedure. It seems though 
that CDC6 has additional roles related to S/M 
checkpoint control. Accumulating evidence suggests 
that CDC6 is required for proper control of mitotic 
entry.Deregulation of CDC6 results in mitotic block, 
aberrant mitotic progression, or apoptosis.  
Homology  
ORC1  
Mutations 
Note: No known mutations. 
Implicated in 
Carcinogenesis 
Note: Because of its key role in DNA replication, 
deregulation of CDC6 could lead to genomic instability 
fueling the risk for neoplastic transformation. Indee , 
CDC6 upregulation has been observed in many 
cancerous lesions, including brain tumors, non-small 
cell lung carcinomas, mantle cell lymphomas, and 
various cervical neoplasias. Interestingly, in aggressive 
prostate cancer, CDC6 is downregulated. 
CDC6 encompasses certain oncogenic characteristics 
that manifest themselves when CDC6 expression is 
deregulated. For example, CDC6 induces DNA 
replication in quiescent cells, while in certain occasions 
overexpression of CDC6 leads to DNA overreplication 
in tumour cells. 
While cells have mechanisms to prevent aberrant DNA 
replication, deregulation of CDC6, or /and its partne  in 
pre-RCs, CDT1 may lead to abrogation of the 
antitumor barriers of senescence and apoptosis. In 
addition their stable expression in premalignant 
papilloma cells lead to transformation of these cells, 
which upon injection into nude mice produce tumors, 
an activity that clearly portrays the oncogenic potential 
of CDC6 deregulation. 
Moreover, deregulation of CDC6 may lead to 
inactivation of the INK4/ARF locus through 
recruitment of histone deacetylases HDAC1 and 
HDAC2 and heterochromatinization of the INK4/ARF 
locus. This locus encodes the tumour suppressor genes 
p16INK4a, p15INK4b, and ARF, and inactivation of 
this locus is closely related to cancer. 
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This article should be referenced as such: 
Zachariadis M, Gorgoulis VG. CDC6 (cell division cycle 6 
homolog (S. cerevisiae)). Atlas Genet Cytogenet Oncol 
Haematol.2008;12(5):362-364. 
 


CDC6 (cell division cycle 6 homolog (S. cerevisiae))

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CDC6 (cell division cycle 6 homolog (S. cerevisiae))

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