Alternative titles; symbols
HGNC Approved Gene Symbol: CDC7
Cytogenetic location: 1p22.1 Genomic coordinates (GRCh38): 1:91,500,851-91,525,764 (from NCBI)
The Cdc7 protein kinase is essential for the G1/S transition and initiation of DNA replication during the cell division cycle in S. cerevisiae. Hsk1 is the S. pombe Cdc7 homolog. By searching EST databases for sequences similar to those of Cdc7 and Hsk1, Jiang and Hunter (1997) identified a partial CDC7L1 cDNA. They used the partial cDNA to isolate a full-length cDNA from a HeLa cell library. The predicted 574-amino acid human CDC7L1 protein contains the 11 conserved subdomains found in all protein serine/threonine kinases as well as 3 additional sequences (kinase inserts) between subdomains I and II, VII and VIII, and X and XI. The kinase domains of CDC7L1 and Cdc7 share 44% protein sequence identity. CDC7L1 has a molecular mass of 64 kD by SDS-PAGE. Using immunofluorescence, the authors demonstrated that CDC7L1 was predominantly localized in the nucleus. Immune complexes of epitope-tagged CDC7L1 from mammalian cell lysates phosphorylated histone H1 in vitro. Although the expression levels of CDC7L1 protein appeared to be constant throughout the cell cycle, the protein kinase activity of CDC7L1 increased during S phase. Jiang and Hunter (1997) suggested that CDC7L1 may phosphorylate critical substrate(s) that regulate the G1/S phase transition and/or DNA replication in mammalian cells.
Sato et al. (1997) isolated cDNAs encoding Xenopus and human Cdc7 homologs. Northern blot analysis revealed that CDC7L1 is expressed as 2.4-, 3.5-, and 4.4-kb mRNAs. The 3.5-kb transcript was detected in all tissues tested, while the 2.4-kb mRNA was testis-specific. Sato et al. (1997) determined that CDC7L1 phosphorylates the MCM2 (116945) and MCM3 (602693) proteins in vitro, suggesting that CDC7L1 may regulate DNA replication by modulating MCM functions. Using Northern blot and dot blot analyses, Hess et al. (1998) found that CDC7L1 was expressed in many normal tissues, but was overexpressed in all transformed cell lines tested and in certain tumor types.
Kim et al. (1998) isolated a cDNA encoding a mouse Cdc7-related protein. The predicted mouse protein is 93% identical to CDC7L1 in the kinase conserved domain.
Sheu and Stillman (2010) showed in S. cerevisiae that the amino-terminal serine/threonine-rich domain (NSD) of Mcm4 (602638) has both inhibitory and facilitating roles in DNA replication control and that the sole essential function of the Dbf4/Cdc7 kinase (DDK, Dbf4-dependent protein kinase) is to relieve an inhibitory activity residing within the NSD. By combining an mcm4 mutant lacking the inhibitory activity with mutations that bypass the requirement for cyclin-dependent protein kinases (CDKs) for initiation of DNA replication, Sheu and Stillman (2010) showed that DNA synthesis can occur in G1 phase when CDKs and DDK are limited. However, DDK is still required for efficient S phase progression. In the absence of DDK, CDK phosphorylation at the distal part of the Mcm4 NSD becomes crucial. Moreover, DDK-null cells failed to activate the intra-S-phase checkpoint in the presence of hydroxyurea-induced DNA damage and were unable to survive this challenge. Sheu and Stillman (2010) concluded that their studies establish that the eukaryote-specific NSD of Mcm4 has evolved to integrate several protein kinase regulatory signals for progression through S phase.
By fluorescence in situ hybridization, Kim et al. (1998) mapped the mouse Cdc7l1 gene to chromosome band 5E5. They stated that the CDC7L1 gene is located on human chromosome band 1p22.
Hess, G. F., Drong, R. F., Weiland, K. L., Slightom, J. L., Sclafani, R. A., Hollingsworth, R. E. A human homolog of the yeast CDC7 gene is overexpressed in some tumors and transformed cell lines. Gene 211: 133-140, 1998. [PubMed: 9573348] [Full Text: https://doi.org/10.1016/s0378-1119(98)00094-8]
Jiang, W., Hunter, T. Identification and characterization of a human protein kinase related to budding yeast Cdc7p. Proc. Nat. Acad. Sci. 94: 14320-14325, 1997. [PubMed: 9405610] [Full Text: https://doi.org/10.1073/pnas.94.26.14320]
Kim, J. M., Sato, N., Yamada, M., Arai, K., Masai, H. Growth regulation of the expression of mouse cDNA and gene encoding a serine/threonine kinase related to Saccharomyces cerevisiae CDC7 essential for G(1)/S transition: structure, chromosomal localization, and expression of mouse gene for S. cerevisiae CDC7-related kinase. J. Biol. Chem. 273: 23248-23257, 1998. Note: Erratum: J. Biol. Chem. 273: 27755 only, 1998. [PubMed: 9722556] [Full Text: https://doi.org/10.1074/jbc.273.36.23248]
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: 4340-4351, 1997. [PubMed: 9250678] [Full Text: https://doi.org/10.1093/emboj/16.14.4340]
Sheu, Y.-J., Stillman, B. The Dbf4-Cdc7 kinase promotes S phase by alleviating an inhibitory activity in Mcm4. Nature 463: 113-117, 2010. [PubMed: 20054399] [Full Text: https://doi.org/10.1038/nature08647]