Cell division cycle 7 (Cdc7) is a serine threonine kinase that is essential for the regulation of normal cell cycle progression. Cdc7 kinase is highly conserved during evolution, and the biological role of Cdc7 kinase in humans has been understood by studying lower eukaryotes, especially yeast. Two important regulatory proteins, Dbf4 and Drf1, bind and regulate the kinase activity of human Cdc7, the latter phosphorylates several sites on Mcm2 (minichromosome maintenance protein 2), which is the replicative DNA unwind required for genome duplication One of the six subunits of the enzyme. By regulating DNA synthesis and DNA damage response, two key functions of tumor cell survival, Cdc7 has become an attractive target for pharmacological inhibition.
Proper handling of stalled or damaged replication forks is critical to cell viability. Cells with defects in checkpoint regulation allow DNA damage to enter mitosis through the cell cycle, leading to mitotic disaster and cell death. Checkpoint responses occur at key points in the cell cycle and consist of mediator proteins that activate checkpoint kinases and effector proteins that perform checkpoint effects. Cdc7 kinase has been implicated in two phases of the checkpoint response. Cdc7 interacts with and phosphorylates the claspin, which is required to activate the ATR–Chk1 checkpoint. In a yeast model, phosphorylation of Mrc1 (equivalent to claspin's yeast) depends on the Cdc7 yeast homolog Hsk1, which is required to activate the yeast effect checkpoint kinase Cds1. In other yeast models, Cdc7 plays a role in the continuous activation of Rad53 checkpoints in response to hydroxyurea. In Xenopus egg extracts, Cdc7 is inactivated by the DNA disrupting agent etoposide, while the response to the same agent is down-regulated in human models. Therefore, in non-clinical models, Cdc7 plays an important role in mediating and affecting Cdc7. Checkpoint response. However, it is unclear whether these functions of Cdc7 are equally important in human models. In fact, it has been shown that the blockade of replication forks in human cells does not alter the activity of Cdc7. But it is clear that the loss of Cdc7 function can lead to s-phase arrest, DNA fragmentation, and cell death if the checkpoint response is cancelled.
In germinating yeast, Cdc7 levels remain constant throughout the cell cycle, and the regulation of kinase activity mainly comes from the binding of other proteins that reach peaks and troughs during the cell cycle. The first of these protein regulators was discovered during Cdc7 kinase research in germinating yeast, when the DBF4 gene was discovered when screening arrested mutants in the form of dumbbells (indicating a defect in initiation of DNA synthesis). Transcribed protein Dbf4 (dumbbell-forming factor 4) binds and activates Cdc7 and is regulated by post-transcriptional and post-translational modifications. Dbf4 levels begin to increase during G1, partially explaining why Cdc7 kinase activity is at G1/S boundary.
In controlling the G1/S process, three cyclin-dependent kinases (Cdks) have been identified as key regulators (Cyclin D/Cdk4, cyclin E/Cdk2 and cyclin A/Cdk2). The sequential activation of these kinases results in phosphorylation of retinoblastoma protein (pRb) and its related family members p107 and p130. Subsequently, E2F transcription factors are activated and induce the expression of other genes required for DNA synthesis, including cyclin E. Three Cdks, Cdk2 (also a serine threonine kinase) together with Cdc7 activate the initiation replication complex and initiate the DNA replication and bifurcation process through the regulation of Mcm2. Recently, the protein CINP that interacts with Cdk2 is considered to be a functional link between Cdk2 and Cdc7 in originating excitation and may play a role in the regulation of two kinases in Mcm2 activation.
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