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

2008-01-01   Michael Zachariadis , Vassilis G Gorgoulis 

University of Athens, Faculty of Medicine, Department of Anatomy (MZ) ; Department of Histology, Embryology, Molecular Carcinogenesis Group (VGG)

Identity

HGNC
LOCATION
17q21.2
LOCUSID
ALIAS
CDC18L,HsCDC18,HsCDC6,MGORS5
FUSION GENES

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 3053RefSeq
CR5980291802mRNA
BC0252322861mRNA
HSU779492653mRNA
AF0221092021mRNA

Pseudogene

there are no known pseudogenes

Proteins

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 name
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.

Bibliography

Pubmed IDLast YearTitleAuthors

Other Information

Locus ID:

NCBI: 990
MIM: 602627
HGNC: 1744
Ensembl: ENSG00000094804

Variants:

dbSNP: 990
ClinVar: 990
TCGA: ENSG00000094804
COSMIC: CDC6

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000094804ENST00000209728Q99741
ENSG00000094804ENST00000209728A0A024R1S2
ENSG00000094804ENST00000473555J3QR52
ENSG00000094804ENST00000577249J3KTI7
ENSG00000094804ENST00000580824J3QLN7
ENSG00000094804ENST00000649662Q99741
ENSG00000094804ENST00000649662A0A024R1S2

Expression (GTEx)

0
5
10
15
20
25

Pathways

PathwaySourceExternal ID
Cell cycleKEGGko04110
Cell cycleKEGGhsa04110
Cell CycleREACTOMER-HSA-1640170
Cell Cycle CheckpointsREACTOMER-HSA-69620
G2/M CheckpointsREACTOMER-HSA-69481
Activation of ATR in response to replication stressREACTOMER-HSA-176187
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G1-G1/S phasesREACTOMER-HSA-453279
G0 and Early G1REACTOMER-HSA-1538133
G1/S TransitionREACTOMER-HSA-69206
G1/S-Specific TranscriptionREACTOMER-HSA-69205
Activation of the pre-replicative complexREACTOMER-HSA-68962
E2F mediated regulation of DNA replicationREACTOMER-HSA-113510
S PhaseREACTOMER-HSA-69242
Synthesis of DNAREACTOMER-HSA-69239
Switching of origins to a post-replicative stateREACTOMER-HSA-69052
Orc1 removal from chromatinREACTOMER-HSA-68949
CDK-mediated phosphorylation and removal of Cdc6REACTOMER-HSA-69017
Regulation of DNA replicationREACTOMER-HSA-69304
Association of licensing factors with the pre-replicative complexREACTOMER-HSA-69298
Removal of licensing factors from originsREACTOMER-HSA-69300
M/G1 TransitionREACTOMER-HSA-68874
DNA Replication Pre-InitiationREACTOMER-HSA-69002
Assembly of the pre-replicative complexREACTOMER-HSA-68867
CDC6 association with the ORC:origin complexREACTOMER-HSA-68689
CDT1 association with the CDC6:ORC:origin complexREACTOMER-HSA-68827
DNA ReplicationREACTOMER-HSA-69306

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
180068352007Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior.78
180483872008CDC6: from DNA replication to cell cycle checkpoints and oncogenesis.73
175679512007Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA damage.62
193430712009Acetylation by GCN5 regulates CDC6 phosphorylation in the S phase of the cell cycle.41
222011242011Cdc6 expression represses E-cadherin transcription and activates adjacent replication origins.36
117798702002Nuclear organization of DNA replication initiation proteins in mammalian cells.34
125546702003Human replication protein Cdc6 prevents mitosis through a checkpoint mechanism that implicates Chk1.31
160557072005p53-Dependent regulation of Cdc6 protein stability controls cellular proliferation.30
147493772004Cdc6 chromatin affinity is unaffected by serine-54 phosphorylation, S-phase progression, and overexpression of cyclin A.28
186175142008Cdt1 and Cdc6 are destabilized by rereplication-induced DNA damage.27

Citation

Michael Zachariadis ; Vassilis G Gorgoulis

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

Atlas Genet Cytogenet Oncol Haematol. 2008-01-01

Online version: http://atlasgeneticsoncology.org/gene/40014/css/lib/bootstrap.min.css