CDC6 (cell division cycle 6 homolog (S. cerevisiae))
2008-01-01 Michael Zachariadis  , Vassilis G Gorgoulis   AffiliationUniversity 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.
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
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.
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.
- 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.
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.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 16179249 | 2005 | CDKs give Cdc6 a license to drive into S phase. | Ayad NG et al |
| 17136093 | 2006 | Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. | Bartkova J et al |
| 11846807 | 2002 | Synthesis and turn-over of the replicative Cdc6 protein during the HeLa cell cycle. | Biermann E et al |
| 12006651 | 2002 | Targeted destruction of DNA replication protein Cdc6 by cell death pathways in mammals and yeast. | Blanchard F et al |
| 12296751 | 2002 | Immunohistochemical localization of cdc6 in squamous and glandular neoplasia of the uterine cervix. | Bonds L et al |
| 18048387 | 2008 | CDC6: from DNA replication to cell cycle checkpoints and oncogenesis. | Borlado LR et al |
| 12554670 | 2003 | Human replication protein Cdc6 prevents mitosis through a checkpoint mechanism that implicates Chk1. | Clay-Farrace L et al |
| 14672932 | 2004 | The regulated association of Cdt1 with minichromosome maintenance proteins and Cdc6 in mammalian cells. | Cook JG et al |
| 11805305 | 2002 | Analysis of Cdc6 function in the assembly of mammalian prereplication complexes. | Cook JG et al |
| 10806104 | 2000 | Chromatin-bound Cdc6 persists in S and G2 phases in human cells, while soluble Cdc6 is destroyed in a cyclin A-cdk2 dependent process. | Coverley D et al |
| 11346650 | 2001 | Multiple mechanisms regulate subcellular localization of human CDC6. | Delmolino LM et al |
| 16055707 | 2005 | p53-Dependent regulation of Cdc6 protein stability controls cellular proliferation. | Duursma A et al |
| 11779870 | 2002 | Nuclear organization of DNA replication initiation proteins in mammalian cells. | Fujita M et al |
| 10464337 | 1999 | Cell cycle regulation of human CDC6 protein. Intracellular localization, interaction with the human mcm complex, and CDC2 kinase-mediated hyperphosphorylation. | Fujita M et al |
| 16572177 | 2006 | Oncogenic activity of Cdc6 through repression of the INK4/ARF locus. | Gonzalez S et al |
| 17567951 | 2007 | Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA damage. | Hall JR et al |
| 9774682 | 1998 | Cell cycle-regulated expression of mammalian CDC6 is dependent on E2F. | Hateboer G et al |
| 11102512 | 2000 | Mutation of cyclin/cdk phosphorylation sites in HsCdc6 disrupts a late step in initiation of DNA replication in human cells. | Herbig U et al |
| 10436018 | 1999 | The Cdc6 nucleotide-binding site regulates its activity in DNA replication in human cells. | Herbig U et al |
| 10339564 | 1999 | Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6. | Jiang W et al |
| 15466399 | 2004 | 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 et al |
| 16439999 | 2006 | The functional role of Cdc6 in S-G2/M in mammalian cells. | Lau E et al |
| 18006835 | 2007 | Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior. | Liontos M et al |
| 11046155 | 2000 | Chromatin association of human origin recognition complex, cdc6, and minichromosome maintenance proteins during the cell cycle: assembly of prereplication complexes in late mitosis. | Méndez J et al |
| 16153703 | 2005 | CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis. | Mailand N et al |
| 15696126 | 2005 | Quantitation of CDC6 and MCM5 mRNA in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix. | Murphy N et al |
| 11496317 | 2001 | Cdc6 expression as a marker of proliferative activity in brain tumors. | Ohta S et al |
| 9778043 | 1998 | Regulation of cell growth-dependent expression of mammalian CDC6 gene by the cell cycle transcription factor E2F. | Ohtani K et al |
| 12628342 | 2003 | Down to the origin: Cdc6 protein and the competence to replicate. | Pelizon C et al |
| 10995389 | 2000 | Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1. | Petersen BO et al |
| 17036332 | 2006 | Unbalanced expression of licensing DNA replication factors occurs in a subset of mantle cell lymphomas with genomic instability. | Pinyol M et al |
| 12006585 | 2002 | Down-regulation of Cdc6, a cell cycle regulatory gene, in prostate cancer. | Robles LD et al |
| 9566895 | 1998 | Human CDC6/Cdc18 associates with Orc1 and cyclin-cdk and is selectively eliminated from the nucleus at the onset of S phase. | Saha P et al |
| 16322558 | 2005 | Recruitment of ORC or CDC6 to DNA is sufficient to create an artificial origin of replication in mammalian cells. | Takeda DY et al |
| 10214964 | 1999 | Identification of the sequence responsible for the nuclear localization of human Cdc6. | Takei Y et al |
| 12718885 | 2003 | A p53-dependent checkpoint pathway prevents rereplication. | Vaziri C et al |
| 8990175 | 1997 | A human protein related to yeast Cdc6p. | Williams RS et al |
| 9520412 | 1998 | Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells. | Yan Z et al |
| 16801388 | 2006 | Cleavage of Cdc6 by caspase-3 promotes ATM/ATR kinase-mediated apoptosis of HeLa cells. | Yim H et al |
Other Information
Locus ID:
NCBI: 990
MIM: 602627
HGNC: 1744
Ensembl: ENSG00000094804
Variants:
dbSNP: 990
ClinVar: 990
TCGA: ENSG00000094804
COSMIC: CDC6
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38186304 | 2024 | CDC6 may serve as an indicator of lung adenocarcinoma prognosis and progression based on TCGA and GEO data mining and experimental analyses. | 1 |
| 38186304 | 2024 | CDC6 may serve as an indicator of lung adenocarcinoma prognosis and progression based on TCGA and GEO data mining and experimental analyses. | 1 |
| 37861550 | 2023 | Role of TOP2A and CDC6 in liver cancer. | 1 |
| 37861550 | 2023 | Role of TOP2A and CDC6 in liver cancer. | 1 |
| 35034031 | 2022 | The Effect of High CDC6 Levels on Predicting Poor Prognosis in Colorectal Cancer. | 5 |
| 35639418 | 2022 | FOXM1 Promotes Malignant Proliferation of Esophageal Squamous Cell Carcinoma Through Transcriptional Activating CDC6. | 4 |
| 35879762 | 2022 | CDC6 is a prognostic biomarker and correlated with immune infiltrates in glioma. | 12 |
| 35034031 | 2022 | The Effect of High CDC6 Levels on Predicting Poor Prognosis in Colorectal Cancer. | 5 |
| 35639418 | 2022 | FOXM1 Promotes Malignant Proliferation of Esophageal Squamous Cell Carcinoma Through Transcriptional Activating CDC6. | 4 |
| 35879762 | 2022 | CDC6 is a prognostic biomarker and correlated with immune infiltrates in glioma. | 12 |
| 32661826 | 2021 | CDC6 is up-regulated and a poor prognostic signature in glioblastoma multiforme. | 8 |
| 33761311 | 2021 | Multiple, short protein binding motifs in ORC1 and CDC6 control the initiation of DNA replication. | 24 |
| 33991762 | 2021 | MiR-128-3p suppresses tumor proliferation and metastasis via targeting CDC6 in hepatocellular carcinoma cells. | 6 |
| 34265399 | 2021 | UHRF1 promotes androgen receptor-regulated CDC6 transcription and anti-androgen receptor drug resistance in prostate cancer through KDM4C-Mediated chromatin modifications. | 0 |
| 32661826 | 2021 | CDC6 is up-regulated and a poor prognostic signature in glioblastoma multiforme. | 8 |
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/cdc6
