Atlas of Genetics and Cytogenetics in Oncology and Haematology
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CDC6 (cell division cycle 6 homolog (S. cerevisiae))
| Identity |
| Other names | CDC18L |
| cdc6 | |
| hCDC6 | |
| HsCDC18 | |
| HsCDC6 | |
| p62 | |
| HGNC (Hugo) | CDC6 |
| LocusID (NCBI) | 990 |
| Location | 17q21.2 |
| Location_base_pair | Starts at 38444146 and ends at 38459413 bp from pter ( according to hg19-Feb_2009) [Mapping] |
| 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.
| ||||||||||||||||||
| 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 |
| Bibliography |
| A human protein related to yeast Cdc6p. |
| Williams RS, Shohet RV, Stillman B |
| Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (1) : 142-147. |
| PMID 8990175 |
| Cell cycle-regulated expression of mammalian CDC6 is dependent on E2F. |
| Hateboer G, Wobst A, Petersen BO, Le Cam L, Vigo E, Sardet C, Helin K |
| Molecular and cellular biology. 1998 ; 18 (11) : 6679-6697. |
| PMID 9774682 |
| Regulation of cell growth-dependent expression of mammalian CDC6 gene by the cell cycle transcription factor E2F. |
| Ohtani K, Tsujimoto A, Ikeda M, Nakamura M |
| Oncogene. 1998 ; 17 (14) : 1777-1785. |
| PMID 9778043 |
| Human CDC6/Cdc18 associates with Orc1 and cyclin-cdk and is selectively eliminated from the nucleus at the onset of S phase. |
| Saha P, Chen J, Thome KC, Lawlis SJ, Hou ZH, Hendricks M, Parvin JD, Dutta A |
| Molecular and cellular biology. 1998 ; 18 (5) : 2758-2767. |
| PMID 9566895 |
| Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells. |
| Yan Z, DeGregori J, Shohet R, Leone G, Stillman B, Nevins JR, Williams RS |
| Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (7) : 3603-3608. |
| PMID 9520412 |
| Cell cycle regulation of human CDC6 protein. Intracellular localization, interaction with the human mcm complex, and CDC2 kinase-mediated hyperphosphorylation. |
| Fujita M, Yamada C, Goto H, Yokoyama N, Kuzushima K, Inagaki M, Tsurumi T |
| The Journal of biological chemistry. 1999 ; 274 (36) : 25927-25932. |
| PMID 10464337 |
| The Cdc6 nucleotide-binding site regulates its activity in DNA replication in human cells. |
| Herbig U, Marlar CA, Fanning E |
| Molecular biology of the cell. 1999 ; 10 (8) : 2631-2645. |
| PMID 10436018 |
| Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6. |
| Jiang W, Wells NJ, Hunter T |
| Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (11) : 6193-6198. |
| PMID 10339564 |
| Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization. |
| Petersen BO, Lukas J, Sˆ½rensen CS, Bartek J, Helin K |
| The EMBO journal. 1999 ; 18 (2) : 396-410. |
| PMID 9889196 |
| Identification of the sequence responsible for the nuclear localization of human Cdc6. |
| Takei Y, Yamamoto K, Tsujimoto G |
| FEBS letters. 1999 ; 447 (2-3) : 292-296. |
| PMID 10214964 |
| 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, Pelizon C, Trewick S, Laskey RA |
| Journal of cell science. 2000 ; 113 ( Pt 11) : 1929-1938. |
| PMID 10806104 |
| Mutation of cyclin/cdk phosphorylation sites in HsCdc6 disrupts a late step in initiation of DNA replication in human cells. |
| Herbig U, Griffith JW, Fanning E |
| Molecular biology of the cell. 2000 ; 11 (12) : 4117-4130. |
| PMID 11102512 |
| Chromatin association of human origin recognition complex, cdc6, and minichromosome maintenance proteins during the cell cycle: assembly of prereplication complexes in late mitosis. |
| Mˆ©ndez J, Stillman B |
| Molecular and cellular biology. 2000 ; 20 (22) : 8602-8612. |
| PMID 11046155 |
| Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1. |
| Petersen BO, Wagener C, Marinoni F, Kramer ER, Melixetian M, Lazzerini Denchi E, Gieffers C, Matteucci C, Peters JM, Helin K |
| Genes & development. 2000 ; 14 (18) : 2330-2343. |
| PMID 10995389 |
| Multiple mechanisms regulate subcellular localization of human CDC6. |
| Delmolino LM, Saha P, Dutta A |
| The Journal of biological chemistry. 2001 ; 276 (29) : 26947-26954. |
| PMID 11346650 |
| Cdc6 expression as a marker of proliferative activity in brain tumors. |
| Ohta S, Koide M, Tokuyama T, Yokota N, Nishizawa S, Namba H |
| Oncology reports. 2001 ; 8 (5) : 1063-1066. |
| PMID 11496317 |
| Synthesis and turn-over of the replicative Cdc6 protein during the HeLa cell cycle. |
| Biermann E, Baack M, Kreitz S, Knippers R |
| European journal of biochemistry / FEBS. 2002 ; 269 (3) : 1040-1046. |
| PMID 11846807 |
| Targeted destruction of DNA replication protein Cdc6 by cell death pathways in mammals and yeast. |
| Blanchard F, Rusiniak ME, Sharma K, Sun X, Todorov I, Castellano MM, Gutierrez C, Baumann H, Burhans WC |
| Molecular biology of the cell. 2002 ; 13 (5) : 1536-1549. |
| PMID 12006651 |
| Immunohistochemical localization of cdc6 in squamous and glandular neoplasia of the uterine cervix. |
| Bonds L, Baker P, Gup C, Shroyer KR |
| Archives of pathology & laboratory medicine. 2002 ; 126 (10) : 1164-1168. |
| PMID 12296751 |
| Analysis of Cdc6 function in the assembly of mammalian prereplication complexes. |
| Cook JG, Park CH, Burke TW, Leone G, DeGregori J, Engel A, Nevins JR |
| Proceedings of the National Academy of Sciences of the United States of America. 2002 ; 99 (3) : 1347-1352. |
| PMID 11805305 |
| Nuclear organization of DNA replication initiation proteins in mammalian cells. |
| Fujita M, Ishimi Y, Nakamura H, Kiyono T, Tsurumi T |
| The Journal of biological chemistry. 2002 ; 277 (12) : 10354-10361. |
| PMID 11779870 |
| Down-regulation of Cdc6, a cell cycle regulatory gene, in prostate cancer. |
| Robles LD, Frost AR, Davila M, Hutson AD, Grizzle WE, Chakrabarti R |
| The Journal of biological chemistry. 2002 ; 277 (28) : 25431-25438. |
| PMID 12006585 |
| Human replication protein Cdc6 prevents mitosis through a checkpoint mechanism that implicates Chk1. |
| Clay-Farrace L, Pelizon C, Santamaria D, Pines J, Laskey RA |
| The EMBO journal. 2003 ; 22 (3) : 704-712. |
| PMID 12554670 |
| Down to the origin: Cdc6 protein and the competence to replicate. |
| Pelizon C |
| Trends in cell biology. 2003 ; 13 (3) : 110-113. |
| PMID 12628342 |
| A p53-dependent checkpoint pathway prevents rereplication. |
| Vaziri C, Saxena S, Jeon Y, Lee C, Murata K, Machida Y, Wagle N, Hwang DS, Dutta A |
| Molecular cell. 2003 ; 11 (4) : 997-1008. |
| PMID 12718885 |
| The regulated association of Cdt1 with minichromosome maintenance proteins and Cdc6 in mammalian cells. |
| Cook JG, Chasse DA, Nevins JR |
| The Journal of biological chemistry. 2004 ; 279 (10) : 9625-9633. |
| PMID 14672932 |
| 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, Taraviras S, Vassiliou LV, Zacharatos P, Kastrinakis NG, Kougiou D, Kouloukoussa M, Nishitani H, Papavassiliou AG, Lygerou Z, Gorgoulis VG |
| The American journal of pathology. 2004 ; 165 (4) : 1351-1365. |
| PMID 15466399 |
| CDKs give Cdc6 a license to drive into S phase. |
| Ayad NG |
| Cell. 2005 ; 122 (6) : 825-827. |
| PMID 16179249 |
| p53-Dependent regulation of Cdc6 protein stability controls cellular proliferation. |
| Duursma A, Agami R |
| Molecular and cellular biology. 2005 ; 25 (16) : 6937-6947. |
| PMID 16055707 |
| CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis. |
| Mailand N, Diffley JF |
| Cell. 2005 ; 122 (6) : 915-926. |
| PMID 16153703 |
| Quantitation of CDC6 and MCM5 mRNA in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix. |
| Murphy N, Ring M, Heffron CC, Martin CM, McGuinness E, Sheils O, O'Leary JJ |
| Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2005 ; 18 (6) : 844-849. |
| PMID 15696126 |
| Recruitment of ORC or CDC6 to DNA is sufficient to create an artificial origin of replication in mammalian cells. |
| Takeda DY, Shibata Y, Parvin JD, Dutta A |
| Genes & development. 2005 ; 19 (23) : 2827-2836. |
| PMID 16322558 |
| Oncogenic activity of Cdc6 through repression of the INK4/ARF locus. |
| Gonzalez S, Klatt P, Delgado S, Conde E, Lopez-Rios F, Sanchez-Cespedes M, Mendez J, Antequera F, Serrano M |
| Nature. 2006 ; 440 (7084) : 702-706. |
| PMID 16572177 |
| The functional role of Cdc6 in S-G2/M in mammalian cells. |
| Lau E, Zhu C, Abraham RT, Jiang W |
| EMBO reports. 2006 ; 7 (4) : 425-430. |
| PMID 16439999 |
| Unbalanced expression of licensing DNA replication factors occurs in a subset of mantle cell lymphomas with genomic instability. |
| Pinyol M, Salaverria I, Bea S, Fernˆ°ndez V, Colomo L, Campo E, Jares P |
| International journal of cancer. Journal international du cancer. 2006 ; 119 (12) : 2768-2774. |
| PMID 17036332 |
| Cleavage of Cdc6 by caspase-3 promotes ATM/ATR kinase-mediated apoptosis of HeLa cells. |
| Yim H, Hwang IS, Choi JS, Chun KH, Jin YH, Ham YM, Lee KY, Lee SK |
| The Journal of cell biology. 2006 ; 174 (1) : 77-88. |
| PMID 16801388 |
| Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. |
| Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, Vassiliou LV, Kolettas E, Niforou K, Zoumpourlis VC, Takaoka M, Nakagawa H, Tort F, Fugger K, Johansson F, Sehested M, Andersen CL, Dyrskjot L, ˆòrntoft T, Lukas J, Kittas C, Helleday T, Halazonetis TD, Bartek J, Gorgoulis VG |
| Nature. 2006 ; 444 (7119) : 633-637. |
| PMID 17136093 |
| CDC6: from DNA replication to cell cycle checkpoints and oncogenesis. |
| Borlado LR, Mˆ©ndez J |
| Carcinogenesis. 2008 ; 29 (2) : 237-243. |
| PMID 18048387 |
| Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA damage. |
| Hall JR, Kow E, Nevis KR, Lu CK, Luce KS, Zhong Q, Cook JG |
| Molecular biology of the cell. 2007 ; 18 (9) : 3340-3350. |
| PMID 17567951 |
| Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior. |
| Liontos M, Koutsami M, Sideridou M, Evangelou K, Kletsas D, Levy B, Kotsinas A, Nahum O, Zoumpourlis V, Kouloukoussa M, Lygerou Z, Taraviras S, Kittas C, Bartkova J, Papavassiliou AG, Bartek J, Halazonetis TD, Gorgoulis VG |
| Cancer research. 2007 ; 67 (22) : 10899-10909. |
| PMID 18006835 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| 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. 2008;12(5):362-364. |
| Free journal version : [ pdf ] [ DOI ] |
| URL : http://AtlasGeneticsOncology.org/Genes/CDC6ID40014ch17q21.html |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Tue Feb 17 20:22:15 CET 2015 |
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