Cell division cycle 7-related protein kinase

Cell division cycle 7 homolog (S. cerevisiae), also known as CDC7, is a human gene.cite web | title = Entrez Gene: CDC7 cell division cycle 7 homolog (S. cerevisiae)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8317| accessdate = ]

PBB_Summary
section_title =
summary_text = The product encoded by this gene is predominantly localized in the nucleus and is a cell division cycle protein with kinase activity. Although expression levels of the protein appear to be constant throughout the cell cycle, the protein kinase activity appears to increase during S phase. It has been suggested that the protein is essential for initiation of DNA replication and that it plays a role in regulating cell cycle progression. Overexpression of this gene product may be associated with neoplastic transformation for some tumors. Additional transcript sizes have been detected, suggesting the presence of alternative splicing.cite web | title = Entrez Gene: CDC7 cell division cycle 7 homolog (S. cerevisiae)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8317| accessdate = ]

General Information About CDC7

Cell division cycle 7 (CDC7) is a gene that codes for the protein Cdc7 kinase. The Cdc7 kinase is involved in regulation of the cell cycleat the point of chromosmal DNA replication [http://www.ncbi.nlm.nih.gov/pubmed/14643427?dopt=Abstract [2] . The cell cycle consists of four different phases including G1, S, G2, and M phase; different functions are able to occur at each phase of the cell’s life. Replication of DNA occurs in the S phase of the cycle. The gene CDC7 appears to be conserved throughout eukaryotic evolution; this means that most eukaryotic cells have the Cdc7 kinase protein. Eukaryotes are cells that have membrane bound compartments that look like “little organs” called organelles; plants, insects, mammls, and yeasts are all examples of eukaryotes. The protein is a serine-threonine kinase that is activated by another protein called either Dbf4 in the yeast "Saccharomyces cerevisiae" or ASK in mammals. The Cdc7/Dbf4 complex adds a phosphate group to the minichromosome maintenance (MCM) protein complex allowing for the initiation of DNA replication in mitosis mitosis (as explained in the Cdc7 and Replication section below). Mitosis is a process of replication where the daughter cells are exact copies, or clones, of the original mother cell.

Cell Cycle Regulation

The gene, CDC7, is involved in the regulation of cell cycle because of the gene product Cdc7 kinase. The protein Cdc kinase is made, expressed, from the CDC7 gene at constant levels throughout the cell cycle. If there is not control of the amount of protein being made in different phases of the cell cycle it is hard to see how it regulates the DNA replication at all. The gene coding for the Dbf4 or ASK protein is regulated during the different phases of cell cycle. The concentration of Dbf4 at the G1/S transition of the cell cycle is higher than the concentration at the M/G1 transition. This tells us that there is Dbf4 expressed around the time for replication, nut after replication is over the protein levels drop. Because the two proteins, Cdc7 and Dbf4, must form a complex before activating the MCM complex the regulation of one protein is sufficient for both. It has been shown that CDC7 is important for replication. There are a number of ways the protein expression has been altered leading to problems. In mouse embryonic stem cells (ESCs) Cdc7 is needed for proliferation. Without the CDC7 gene DNA synthesis is stopped, and the ESCs do not grow. With the loss of function of Cdc7 in ESCs the S phase is stopped at the G2/M checkpoint. Recombinational repair (RR) is done at this point to try to fix the CDC7 gene so replication can occur. By copying and replacing the altered area with a very similar area on the sister homolog chromosome, the gene can be replicated as if nothing was ever wrong on the chromosome. However, when the cell enters this arrested state, levels of p53 may increase. These increased levels of p53 may initiate cell death [http://www.ncbi.nlm.nih.gov/pubmed/14643427?dopt=Abstract [2] .

Cdc7 and Replication

After chromatin undergoes changes in telophase of mitosis, the hexomeric protein complex of MCM proteins 2-7 forms part of the prereplicative complex (preRC) by binding to the chromatin and other aiding proteins (Cdc6 and Cdt1). Mitosis occurs during M phase of the cell cycle and has a number of stages; telophase is the end stage of mitosis when the replication of chromosomes is complete, but separation has not occurred. The MCM complex is termed hexomeric because it is made of six protein subunits. The subunits are MCM proteins numbers 2-7 [http://web.ebscohost.com.proxy.ohiolink.edu:9099/ehost/detail?vid=1&hid=103&sid=8203ee5c-045a-4f4e-8a10-57fd0ba66be1%40sessionmgr103 [3] .

The Cdc7/Dbf4 kinase complex, along with another serine-threonine kinase, Cyclin-dependent kinase (Cdk), phosphorylates the preRC which activates it at the G1/S transition. The Dbf4 tethers itself to part of the preRC, the origin recognition complex (ORC). Since Cdc7 is attached to the Dbf4 protein the entire complex is held in place during replication. This activation of MCM 2 leads to helicase activity of the MCM complex at the origin of replication. Helicase activity is like unzipping the two strands of DNA by hydrolysis of the hydrogen bonds holding them together. This is most likely due to the change in conformation (shape of the protein) allowing the remainder of replication machinery proteins to be loaded. DNA replication can begin after all the necessary proteins are in place [http://www.ncbi.nlm.nih.gov/pubmed/16036617?dopt=Abstract [4] .

References

2. Kim, JM., Yamada, M., and Masai, H., (2003) Functions of mammalian Cdc7 kinase initiation/monitoring of DNA replication and development. Mutat Res, 532, 29-40. [http://www.ncbi.nlm.nih.gov/pubmed/14643427?dopt=Abstract [2] .

3. Takeda, D.Y., and Dutta, A., (2005) DNA replication and progression through S phase. Oncagene, 24. 2827-2843. [http://web.ebscohost.com.proxy.ohiolink.edu [3] .

4. Masai, H., You, Z., and Arai K., (2005) Control of DNA replication: regulation and activation of eukaryotic replicative helicase, MCM. IUBMB Life 57, 323–335. [http://www.ncbi.nlm.nih.gov/pubmed/16036617?dopt=Abstract [4] .

Further reading

PBB_Further_reading
citations =
*cite journal | author=Sato N, Arai K, Masai H |title=Human and Xenopus cDNAs encoding budding yeast Cdc7-related kinases: in vitro phosphorylation of MCM subunits by a putative human homologue of Cdc7. |journal=EMBO J. |volume=16 |issue= 14 |pages= 4340–51 |year= 1997 |pmid= 9250678 |doi= 10.1093/emboj/16.14.4340
*cite journal | author=Jiang W, Hunter T |title=Identification and characterization of a human protein kinase related to budding yeast Cdc7p. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue= 26 |pages= 14320–5 |year= 1998 |pmid= 9405610 |doi=
*cite journal | author=Hess GF, Drong RF, Weiland KL, "et al." |title=A human homolog of the yeast CDC7 gene is overexpressed in some tumors and transformed cell lines. |journal=Gene |volume=211 |issue= 1 |pages= 133–40 |year= 1998 |pmid= 9573348 |doi=
*cite journal | author=Kumagai H, Sato N, Yamada M, "et al." |title=A novel growth- and cell cycle-regulated protein, ASK, activates human Cdc7-related kinase and is essential for G1/S transition in mammalian cells. |journal=Mol. Cell. Biol. |volume=19 |issue= 7 |pages= 5083–95 |year= 1999 |pmid= 10373557 |doi=
*cite journal | author=Jiang W, McDonald D, Hope TJ, Hunter T |title=Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication. |journal=EMBO J. |volume=18 |issue= 20 |pages= 5703–13 |year= 1999 |pmid= 10523313 |doi= 10.1093/emboj/18.20.5703
*cite journal | author=Masai H, Matsui E, You Z, "et al." |title=Human Cdc7-related kinase complex. In vitro phosphorylation of MCM by concerted actions of Cdks and Cdc7 and that of a criticial threonine residue of Cdc7 bY Cdks. |journal=J. Biol. Chem. |volume=275 |issue= 37 |pages= 29042–52 |year= 2000 |pmid= 10846177 |doi= 10.1074/jbc.M002713200
*cite journal | author=Ishimi Y, Komamura-Kohno Y, Arai K, Masai H |title=Biochemical activities associated with mouse Mcm2 protein. |journal=J. Biol. Chem. |volume=276 |issue= 46 |pages= 42744–52 |year= 2001 |pmid= 11568184 |doi= 10.1074/jbc.M106861200
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*cite journal | author=Ramachandran N, Hainsworth E, Bhullar B, "et al." |title=Self-assembling protein microarrays. |journal=Science |volume=305 |issue= 5680 |pages= 86–90 |year= 2004 |pmid= 15232106 |doi= 10.1126/science.1097639
*cite journal | author=Montagnoli A, Tenca P, Sola F, "et al." |title=Cdc7 inhibition reveals a p53-dependent replication checkpoint that is defective in cancer cells. |journal=Cancer Res. |volume=64 |issue= 19 |pages= 7110–6 |year= 2004 |pmid= 15466207 |doi= 10.1158/0008-5472.CAN-04-1547
*cite journal | author=Kurita M, Suzuki H, Masai H, "et al." |title=Overexpression of CR/periphilin downregulates Cdc7 expression and induces S-phase arrest. |journal=Biochem. Biophys. Res. Commun. |volume=324 |issue= 2 |pages= 554–61 |year= 2004 |pmid= 15474462 |doi= 10.1016/j.bbrc.2004.09.083
*cite journal | author=Gerhard DS, Wagner L, Feingold EA, "et al." |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504
*cite journal | author=Yoshizawa-Sugata N, Ishii A, Taniyama C, "et al." |title=A second human Dbf4/ASK-related protein, Drf1/ASKL1, is required for efficient progression of S and M phases. |journal=J. Biol. Chem. |volume=280 |issue= 13 |pages= 13062–70 |year= 2005 |pmid= 15668232 |doi= 10.1074/jbc.M411653200
*cite journal | author=Grishina I, Lattes B |title=A novel Cdk2 interactor is phosphorylated by Cdc7 and associates with components of the replication complexes. |journal=Cell Cycle |volume=4 |issue= 8 |pages= 1120–6 |year= 2006 |pmid= 16082200 |doi=
*cite journal | author=Montagnoli A, Valsasina B, Brotherton D, "et al." |title=Identification of Mcm2 phosphorylation sites by S-phase-regulating kinases. |journal=J. Biol. Chem. |volume=281 |issue= 15 |pages= 10281–90 |year= 2006 |pmid= 16446360 |doi= 10.1074/jbc.M512921200
*cite journal | author=Gregory SG, Barlow KF, McLay KE, "et al." |title=The DNA sequence and biological annotation of human chromosome 1. |journal=Nature |volume=441 |issue= 7091 |pages= 315–21 |year= 2006 |pmid= 16710414 |doi= 10.1038/nature04727
*cite journal | author=Gérard A, Koundrioukoff S, Ramillon V, "et al." |title=The replication kinase Cdc7-Dbf4 promotes the interaction of the p150 subunit of chromatin assembly factor 1 with proliferating cell nuclear antigen. |journal=EMBO Rep. |volume=7 |issue= 8 |pages= 817–23 |year= 2006 |pmid= 16826239 |doi= 10.1038/sj.embor.7400750
*cite journal | author=Cho WH, Lee YJ, Kong SI, "et al." |title=CDC7 kinase phosphorylates serine residues adjacent to acidic amino acids in the minichromosome maintenance 2 protein. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue= 31 |pages= 11521–6 |year= 2006 |pmid= 16864800 |doi= 10.1073/pnas.0604990103

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