Cell division cycle 7-related protein kinase

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Cell division cycle 7
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CDC7 ; CDC7L1; HsCDC7; Hsk1; huCDC7
External IDs OMIM603311 MGI1309511 HomoloGene31166 ChEMBL: 5443 GeneCards: CDC7 Gene
EC number 2.7.11.1
RNA expression pattern
PBB GE CDC7 204510 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 8317 12545
Ensembl ENSG00000097046 ENSMUSG00000029283
UniProt O00311 Q9Z0H0
RefSeq (mRNA) NM_001134419 NM_001271566
RefSeq (protein) NP_001127891 NP_001258495
Location (UCSC) Chr 1:
91.97 – 91.99 Mb
Chr 5:
106.96 – 106.98 Mb
PubMed search [1] [2]

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 chromosmal 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[edit]

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[edit]

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[edit]

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).[5] 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.[6]

Interactions[edit]

CDC7 has been shown to interact with:

References[edit]

  1. ^ Jiang W, Hunter T (Feb 1998). "Identification and characterization of a human protein kinase related to budding yeast Cdc7p". Proc Natl Acad Sci U S A 94 (26): 14320–5. doi:10.1073/pnas.94.26.14320. PMC 24960. PMID 9405610. 
  2. ^ Sato N, Arai K, Masai H (Sep 1997). "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. doi:10.1093/emboj/16.14.4340. PMC 1170060. PMID 9250678. 
  3. ^ a b "Entrez Gene: CDC7 cell division cycle 7 homolog (S. cerevisiae)". 
  4. ^ a b Kim JM, Yamada M, Masai H (November 2003). "Functions of mammalian Cdc7 kinase in initiation/monitoring of DNA replication and development". Mutat. Res. 532 (1-2): 29–40. doi:10.1016/j.mrfmmm.2003.08.008. PMID 14643427. 
  5. ^ http://web.ebscohost.com.proxy.ohiolink.edu:9099/ehost/detail?vid=1&hid=103&sid=8203ee5c-045a-4f4e-8a10-57fd0ba66be1%40sessionmgr103[dead link]
  6. ^ Masai H, You Z, Arai K (2005). "Control of DNA replication: regulation and activation of eukaryotic replicative helicase, MCM". IUBMB Life 57 (4-5): 323–35. doi:10.1080/15216540500092419. PMID 16036617. 
  7. ^ a b c d e f Kneissl M, Pütter V, Szalay AA, Grummt F (March 2003). "Interaction and assembly of murine pre-replicative complex proteins in yeast and mouse cells". J. Mol. Biol. 327 (1): 111–28. doi:10.1016/S0022-2836(03)00079-2. PMID 12614612. 
  8. ^ Kumagai H, Sato N, Yamada M, Mahony D, Seghezzi W, Lees E, Arai K, Masai H (July 1999). "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. PMC 84351. PMID 10373557. 
  9. ^ Jiang W, McDonald D, Hope TJ, Hunter T (October 1999). "Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication". EMBO J. 18 (20): 5703–13. doi:10.1093/emboj/18.20.5703. PMC 1171637. PMID 10523313. 

Further reading[edit]