Cell division cycle 7-related protein kinase explained

Cell division cycle 7-related protein kinase is an enzyme that in humans is encoded by the CDC7 gene.^{[1] [2] [3]} The Cdc7 kinase is involved in regulation of the cell cycle at the point of chromosomal DNA replication.^[4] The gene CDC7 appears to be conserved throughout eukaryotic evolution; this means that most eukaryotic cells have the Cdc7 kinase protein.

Function

The product encoded by this gene is predominantly localized in the nucleus and is a cell division cycle protein with kinase activity. 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 (as explained in the Cdc7 and Replication section below).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.^[3]

Cell cycle regulation

The gene, CDC7, is involved in the regulation of cell cycle because of the gene product Cdc7 kinase. The protein is expressed at constant levels throughout the cell cycle. 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 Dbf4 is expressed around the time for replication; right 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 several ways its expression can be altered that leads 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.^[4]

Replication

After chromatin undergoes changes in telophase of mitosis, the hexameric protein complex of MCM proteins 2-7 forms part of the pre-replication complex (pre-RC) 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 Cdc7/Dbf4 kinase complex, along with another serine-threonine kinase, cyclin-dependent kinase (Cdk), phosphorylates the pre-RC which activates it at the G1/S transition. The Dbf4 tethers itself to part of the pre-RC, 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. This is most likely due to the change in conformation allowing the remainder of replication machinery proteins to be loaded. DNA replication can begin after all the necessary proteins are in place.^[5]

Interactions

CDC7 has been shown to interact with:

• DBF4,^{[6] [7]}
• MCM5,^[8]
• MCM4,^[8]
• MCM7,^[8]
• ORC1L,^[8] and
• ORC6L.^[8]

Ligands

Inhibitors

• XL-413

Further reading

• Sato N, Arai K, Masai H . Human and Xenopus cDNAs encoding budding yeast Cdc7-related kinases: in vitro phosphorylation of MCM subunits by a putative human homologue of Cdc7 . EMBO J. . 16 . 14 . 4340–51 . 1997 . 9250678 . 1170060 . 10.1093/emboj/16.14.4340 .
• Jiang W, Hunter T . Identification and characterization of a human protein kinase related to budding yeast Cdc7p . Proc. Natl. Acad. Sci. U.S.A. . 94 . 26 . 14320–5 . 1997 . 9405610 . 24960 . 10.1073/pnas.94.26.14320 . 1997PNAS...9414320J . free .
• Hess GF, Drong RF, Weiland KL, Slightom JL, Sclafani RA, Hollingsworth RE . A human homolog of the yeast CDC7 gene is overexpressed in some tumors and transformed cell lines . Gene . 211 . 1 . 133–40 . 1998 . 9573348 . 10.1016/S0378-1119(98)00094-8 .
• Kumagai H, Sato N, Yamada M, Mahony D, Seghezzi W, Lees E, Arai K, Masai H . A novel growth- and cell cycle-regulated protein, ASK, activates human Cdc7-related kinase and is essential for G1/S transition in mammalian cells . Mol. Cell. Biol. . 19 . 7 . 5083–95 . 1999 . 10373557 . 84351 . 10.1128/MCB.19.7.5083.
• Jiang W, McDonald D, Hope TJ, Hunter T . Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication . EMBO J. . 18 . 20 . 5703–13 . 1999 . 10523313 . 1171637 . 10.1093/emboj/18.20.5703 .
• Masai H, Matsui E, You Z, Ishimi Y, Tamai K, Arai K . Human Cdc7-related kinase complex. In vitro phosphorylation of MCM by concerted actions of Cdks and Cdc7 and that of a critical threonine residue of Cdc7 bY Cdks . J. Biol. Chem. . 275 . 37 . 29042–52 . 2000 . 10846177 . 10.1074/jbc.M002713200 . free .
• Ishimi Y, Komamura-Kohno Y, Arai K, Masai H . Biochemical activities associated with mouse Mcm2 protein . J. Biol. Chem. . 276 . 46 . 42744–52 . 2001 . 11568184 . 10.1074/jbc.M106861200 . free .
• Montagnoli A, Bosotti R, Villa F, Rialland M, Brotherton D, Mercurio C, Berthelsen J, Santocanale C . Drf1, a novel regulatory subunit for human Cdc7 kinase . EMBO J. . 21 . 12 . 3171–81 . 2002 . 12065429 . 126049 . 10.1093/emboj/cdf290 .
• Kneissl M, Pütter V, Szalay AA, Grummt F . Interaction and assembly of murine pre-replicative complex proteins in yeast and mouse cells . J. Mol. Biol. . 327 . 1 . 111–28 . 2003 . 12614612 . 10.1016/S0022-2836(03)00079-2 .
• Montagnoli A, Tenca P, Sola F, Carpani D, Brotherton D, Albanese C, Santocanale C . Cdc7 inhibition reveals a p53-dependent replication checkpoint that is defective in cancer cells . Cancer Res. . 64 . 19 . 7110–6 . 2004 . 15466207 . 10.1158/0008-5472.CAN-04-1547 . free .
• Kurita M, Suzuki H, Masai H, Mizumoto K, Ogata E, Nishimoto I, Aiso S, Matsuoka M . Overexpression of CR/periphilin downregulates Cdc7 expression and induces S-phase arrest . Biochem. Biophys. Res. Commun. . 324 . 2 . 554–61 . 2004 . 15474462 . 10.1016/j.bbrc.2004.09.083 .
• Yoshizawa-Sugata N, Ishii A, Taniyama C, Matsui E, Arai K, Masai H . A second human Dbf4/ASK-related protein, Drf1/ASKL1, is required for efficient progression of S and M phases . J. Biol. Chem. . 280 . 13 . 13062–70 . 2005 . 15668232 . 10.1074/jbc.M411653200 . free .
• Grishina I, Lattes B . A novel Cdk2 interactor is phosphorylated by Cdc7 and associates with components of the replication complexes . Cell Cycle . 4 . 8 . 1120–6 . 2005 . 16082200 . 10.4161/cc.4.8.1918 . free .
• Montagnoli A, Valsasina B, Brotherton D, Troiani S, Rainoldi S, Tenca P, Molinari A, Santocanale C . Identification of Mcm2 phosphorylation sites by S-phase-regulating kinases . J. Biol. Chem. . 281 . 15 . 10281–90 . 2006 . 16446360 . 10.1074/jbc.M512921200 . free .
• Gérard A, Koundrioukoff S, Ramillon V, Sergère JC, Mailand N, Quivy JP, Almouzni G . The replication kinase Cdc7-Dbf4 promotes the interaction of the p150 subunit of chromatin assembly factor 1 with proliferating cell nuclear antigen . EMBO Rep. . 7 . 8 . 817–23 . 2006 . 16826239 . 1525143 . 10.1038/sj.embor.7400750 .
• Cho WH, Lee YJ, Kong SI, Hurwitz J, Lee JK . CDC7 kinase phosphorylates serine residues adjacent to acidic amino acids in the minichromosome maintenance 2 protein . Proc. Natl. Acad. Sci. U.S.A. . 103 . 31 . 11521–6 . 2006 . 16864800 . 1544202 . 10.1073/pnas.0604990103 . 2006PNAS..10311521C . free .

Notes and References

1. Jiang W, Hunter T . Identification and characterization of a human protein kinase related to budding yeast Cdc7p . Proc. Natl. Acad. Sci. U.S.A. . 94 . 26 . 14320–5 . Feb 1998 . 9405610 . 24960 . 10.1073/pnas.94.26.14320 . 1997PNAS...9414320J . free .
2. Sato N, Arai K, Masai H . Human and Xenopus cDNAs encoding budding yeast Cdc7-related kinases: in vitro phosphorylation of MCM subunits by a putative human homologue of Cdc7 . EMBO J. . 16 . 14 . 4340–51 . Sep 1997 . 9250678 . 1170060 . 10.1093/emboj/16.14.4340 .
3. Web site: Entrez Gene: CDC7 cell division cycle 7 homolog (S. cerevisiae).
4. Kim JM, Yamada M, Masai H . Functions of mammalian Cdc7 kinase in initiation/monitoring of DNA replication and development . Mutat. Res. . 532 . 1–2 . 29–40 . November 2003 . 14643427 . 10.1016/j.mrfmmm.2003.08.008 .
5. Masai H, You Z, Arai K . Control of DNA replication: regulation and activation of eukaryotic replicative helicase, MCM . IUBMB Life . 57 . 4–5 . 323–35 . 2005 . 16036617 . 10.1080/15216540500092419 . free .
6. Kumagai H, Sato N, Yamada M, Mahony D, Seghezzi W, Lees E, Arai K, Masai H . A novel growth- and cell cycle-regulated protein, ASK, activates human Cdc7-related kinase and is essential for G1/S transition in mammalian cells . Mol. Cell. Biol. . 19 . 7 . 5083–95 . July 1999 . 10373557 . 84351 . 10.1128/MCB.19.7.5083.
7. Jiang W, McDonald D, Hope TJ, Hunter T . Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication . EMBO J. . 18 . 20 . 5703–13 . October 1999 . 10523313 . 1171637 . 10.1093/emboj/18.20.5703 .
8. Kneissl M, Pütter V, Szalay AA, Grummt F . Interaction and assembly of murine pre-replicative complex proteins in yeast and mouse cells . J. Mol. Biol. . 327 . 1 . 111–28 . March 2003 . 12614612 . 10.1016/S0022-2836(03)00079-2 .