Cell division cycle 7-related protein kinase is an enzyme that in humans is encoded by the CDC7 gene. [5] [6] [7] The Cdc7 kinase is involved in regulation of the cell cycle at the point of chromosomal DNA replication. [8] The gene CDC7 appears to be conserved throughout eukaryotic evolution; this means that most eukaryotic cells have the Cdc7 kinase protein.
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. [7]
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. [8]
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).[ citation needed ] 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. [9]
CDC7 has been shown to interact with:
DNA replication licensing factor MCM6 is a protein that in humans is encoded by the MCM6 gene. MCM6 is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication.
In molecular biology, origin recognition complex (ORC) is a multi-subunit DNA binding complex that binds in all eukaryotes and archaea in an ATP-dependent manner to origins of replication. The subunits of this complex are encoded by the ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6 genes. ORC is a central component for eukaryotic DNA replication, and remains bound to chromatin at replication origins throughout the cell cycle.
Eukaryotic DNA replication is a conserved mechanism that restricts DNA replication to once per cell cycle. Eukaryotic DNA replication of chromosomal DNA is central for the duplication of a cell and is necessary for the maintenance of the eukaryotic genome.
The minichromosome maintenance protein complex (MCM) is a DNA helicase essential for genomic DNA replication. Eukaryotic MCM consists of six gene products, Mcm2–7, which form a heterohexamer. As a critical protein for cell division, MCM is also the target of various checkpoint pathways, such as the S-phase entry and S-phase arrest checkpoints. Both the loading and activation of MCM helicase are strictly regulated and are coupled to cell growth cycles. Deregulation of MCM function has been linked to genomic instability and a variety of carcinomas.
Replication protein A 70 kDa DNA-binding subunit is a protein that in humans is encoded by the RPA1 gene.
DNA replication licensing factor MCM7 is a protein that in humans is encoded by the MCM7 gene.
DNA replication licensing factor MCM2 is a protein that in humans is encoded by the MCM2 gene.
DNA replication licensing factor MCM3 is a protein that in humans is encoded by the MCM3 gene.
Cell division control protein 6 homolog is a protein that in humans is encoded by the CDC6 gene.
DNA replication licensing factor MCM4 is a protein that in humans is encoded by the MCM4 gene.
CDT1 is a protein that in humans is encoded by the CDT1 gene. It is a licensing factor that functions to limit DNA from replicating more than once per cell cycle.
Origin recognition complex subunit 2 is a protein that is encoded by the ORC2 (ORC2L) gene in humans.
DNA replication licensing factor MCM5 is a protein that in humans is encoded by the MCM5 gene.
Protein DBF4 homolog A is a protein that is encoded by the DBF4 gene in humans.
Origin recognition complex subunit 4 is a protein that in humans is encoded by the ORC4 (ORC4L) gene.
Origin recognition complex subunit 6 is a protein that in humans is encoded by the ORC6 (ORC6L) gene.
CDC45 is a protein that in humans is encoded by the CDC45L gene.
Cdc6, or cell division cycle 6, is a protein in eukaryotic cells. It is mainly studied in the budding yeast Saccharomyces cerevisiae. It is an essential regulator of DNA replication and plays important roles in the activation and maintenance of the checkpoint mechanisms in the cell cycle that coordinate S phase and mitosis. It is part of the pre-replicative complex (pre-RC) and is required for loading minichromosome maintenance (MCM) proteins onto the DNA, an essential step in the initiation of DNA synthesis. In addition, it is a member of the family of AAA+ ATPases and highly related to ORC1; both are the same protein in archaea.
In cell biology, eukaryotes possess a regulatory system that ensures that DNA replication occurs only once per cell cycle.
Origin recognition complex subunit 1 is a protein that in humans is encoded by the ORC1 gene. It is closely related to CDC6, and both are the same protein in archaea.
