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

Identity

Other names	CDC18L
	cdc6
	hCDC6
	HsCDC18
	HsCDC6
	p62
HGNC	CDC6
Location	17q21.3
Location_base_pair	Starts at 35697672 and ends at 35712939 bp from pter ( according to hg18-Mar_2006).
Local_order	centrosome ---- CASC3-RAPGEFL1-WIPF2-CDC6-RARA-TOP2A

DNA/RNA

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 element, 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 transcripts (see table below) encode the same product of 560aa. There are about 230 EST sequences. Accession N° Transcript length (bp) Notes NM_001254 3053 RefSeq CR598029 1802 mRNA BC025232 2861 mRNA HSU77949 2653 mRNA AF022109 2021 mRNA
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 nucleotide 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 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

Entity	Carcinogenesis
Note	Because of its key role in DNA replication, deregulation of CDC6 could lead to genomic instability fueling the risk for neoplastic transformation. Indeed, 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 partner 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.

External links

	Nomenclature
HGNC	CDC6   1744
Entrez_Gene	CDC6  990  cell division cycle 6 homolog (S. cerevisiae)
	Cards
Atlas	CDC6ID40014ch17q21
GeneCards	CDC6
Ensembl	CDC6 [Search_View]   ENSG00000094804 [Gene_View]  CDC6 [Vega]
Genatlas	CDC6
GeneLynx	CDC6
eGenome	CDC6
euGene	990
	Genomic and cartography
GoldenPath	CDC6  -  17q21.3   chr17:35697672-35712939 +  17q21.3   [Description]    (hg18-Mar_2006)
Ensembl	CDC6 - 17q21.3 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	CDC6
	Gene and transcription
Genbank	AA210818 [ ENTREZ ]
Genbank	AF022109 [ ENTREZ ]
Genbank	AK313620 [ ENTREZ ]
Genbank	BC025232 [ ENTREZ ]
Genbank	BE296640 [ ENTREZ ]
RefSeq	NM_001254 [ SRS ]    NM_001254 [ ENTREZ ]
RefSeq	AC_000060 [ SRS ]    AC_000060 [ ENTREZ ]
RefSeq	AC_000149 [ SRS ]    AC_000149 [ ENTREZ ]
RefSeq	NC_000017 [ SRS ]    NC_000017 [ ENTREZ ]
RefSeq	NT_010755 [ SRS ]    NT_010755 [ ENTREZ ]
RefSeq	NW_001838435 [ SRS ]    NW_001838435 [ ENTREZ ]
RefSeq	NW_926828 [ SRS ]    NW_926828 [ ENTREZ ]
CCDS	CDC6 CCDS - NCBI
AceView	CDC6 AceView - NCBI
Unigene	Hs.405958 [ SRS ]    Hs.405958 [ NCBI ]     HS405958 [ spliceNest ]
Fast-db	9812 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q99741 [ SRS]    Q99741 [ EXPASY ]     Q99741 [ INTERPRO ]     Q99741 [ UNIPROT ] Q99741 [ VarSplice ]
Interpro	IPR003593 AAA+_ATPase_core [ SRS ]    IPR003593 AAA+_ATPase_core [ EBI ]
Interpro	IPR003959 AAA_ATPase_core [ SRS ]    IPR003959 AAA_ATPase_core [ EBI ]
Interpro	IPR016314 Cdc6 [ SRS ]    IPR016314 Cdc6 [ EBI ]
Interpro	IPR015163 Cdc6_C [ SRS ]    IPR015163 Cdc6_C [ EBI ]
CluSTr	Q99741
Pfam	PF00004 AAA [ SRS ]    PF00004 AAA [ Sanger ]    pfam00004 [ NCBI-CDD ]
Pfam	PF09079 Cdc6_C [ SRS ]    PF09079 Cdc6_C [ Sanger ]    pfam09079 [ NCBI-CDD ]
Smart	SM00382 AAA [EMBL]
Blocks	Q99741
PDB	2CCH [ SRS ]    2CCH [ PdbSum ],   2CCH [ IMB ]   2CCH [ RSDB ]
PDB	2CCI [ SRS ]    2CCI [ PdbSum ],   2CCI [ IMB ]   2CCI [ RSDB ]
HPRD	04022
	Protein Interaction databases
DIP	Q99741
IntAct	Q99741
	Polymorphism : SNP, mutations, diseases
OMIM	602627    [ map ]
GENECLINICS	602627
SNP	CDC6 [dbSNP-NCBI]
SNP	NM_001254 [SNP-NCI]
SNP	CDC6 [GeneSNPs - Utah]  CDC6] [HGBASE - SRS]
HAPMAP	CDC6 [HAPMAP]
COSMIC	CDC6 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	CDC6
Genetic Association	CDC6
CDC HuGE	CDC6
	General knowledge
Family Browser	CDC6 [UCSC Family Browser]
SOURCE	NM_001254
SMD	Hs.405958
SAGE	Hs.405958
GO	DNA replication checkpoint [Amigo]  DNA replication checkpoint
GO	regulation of cyclin-dependent protein kinase activity [Amigo]  regulation of cyclin-dependent protein kinase activity
GO	nucleotide binding [Amigo]  nucleotide binding
GO	chromatin binding [Amigo]  chromatin binding
GO	protein binding [Amigo]  protein binding
GO	ATP binding [Amigo]  ATP binding
GO	nucleus [Amigo]  nucleus
GO	nucleoplasm [Amigo]  nucleoplasm
GO	cytoplasm [Amigo]  cytoplasm
GO	spindle [Amigo]  spindle
GO	cytosol [Amigo]  cytosol
GO	cell cycle [Amigo]  cell cycle
GO	mitosis [Amigo]  mitosis
GO	traversing start control point of mitotic cell cycle [Amigo]  traversing start control point of mitotic cell cycle
GO	negative regulation of DNA replication [Amigo]  negative regulation of DNA replication
GO	negative regulation of cell proliferation [Amigo]  negative regulation of cell proliferation
GO	nucleoside-triphosphatase activity [Amigo]  nucleoside-triphosphatase activity
GO	cell division [Amigo]  cell division
BIOCARTA	CDK Regulation of DNA Replication    [Genes]
KEGG	Cell cycle
PubGene	CDC6
TreeFam	CDC6
CTD	990 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	CDC6 Related clones (RZPD - Berlin)
	PubMed
PubMed	56 Pubmed reference(s) in Entrez

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PMID 11046155

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PMID 10995389

Multiple mechanisms regulate subcellular localization of human CDC6.

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PMID 11346650

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Synthesis and turn-over of the replicative Cdc6 protein during the HeLa cell cycle.

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Targeted destruction of DNA replication protein Cdc6 by cell death pathways in mammals and yeast.

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PMID 12006651

Immunohistochemical localization of cdc6 in squamous and glandular neoplasia of the uterine cervix.

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Archives of pathology & laboratory medicine. 2002 ; 126 (10) : 1164-1168.

PMID 12296751

Analysis of Cdc6 function in the assembly of mammalian prereplication complexes.

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Proceedings of the National Academy of Sciences of the United States of America. 2002 ; 99 (3) : 1347-1352.

PMID 11805305

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PMID 11779870

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PMID 12006585

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CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis.

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PMID 16572177

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PMID 16439999

Unbalanced expression of licensing DNA replication factors occurs in a subset of mantle cell lymphomas with genomic instability.

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PMID 17036332

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PMID 16801388

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PMID 17136093

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PMID 18048387

Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA damage.

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Molecular biology of the cell. 2007 ; 18 (9) : 3340-3350.

PMID 17567951

Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior.

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PMID 18006835

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Contributor(s)

Written	01-2008	Michael Zachariadis, Vassilis G Gorgoulis
		University of Athens, Faculty of Medicine, Department of Anatomy (MZ) ; Department of Histology and Embryology, Molecular Carcinogenesis Group (VGG)

Citation

This paper should be referenced as such :

Zachariadis M, Gorgoulis VG . CDC6 (cell division cycle 6 homolog (S. cerevisiae)). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/CDC6ID40014ch17q21.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Sun Nov 9 19:38:35 2008