All stages of the cell cycle in normal cells are tightly controlled. In cancer cells, several proteins and genes that impact the progression of the cell cycle are overexpressed or mutated and turn into oncogenes. The proteins involved in cell cycle regulation, specifically DNA damage and DNA replication, are significant cancer therapeutic targets.
Cell Cycle Progression and DNA Repair
G1/S, intra-S phase, and G2/M phase are three important regulatory cell cycle checkpoints. A cell can pass through these checkpoints only in the presence of stimulatory signals and in the absence of DNA damage. The cyclin-dependent kinases (cdks) family and tumor suppressor proteins control these cell cycle checkpoints. Cdks function in tandem with their regulatory subunits, cyclins, in controlling cell cycle progression. Cdks are constitutively expressed and controlled by different phosphatases and kinases, including Cdc25 phosphatase and Wee1 kinase.
DNA damage is detected and repaired at particular points in the cell cycle. This process is triggered by ATM kinase and ATR kinase, and DNA damage sensors. Signaling cascades are initiated by the checkpoint kinases Chk1 and Chk2, in turn activating DNA damage checkpoints in G1 and G2. The spindle assembly checkpoint (SAC) prevents the anaphase of mitosis until the correct arrangement of all chromosomes on the spindle occurs, thus preventing aneuploidy. Kinases including polo-like kinase (PLK1), aurora kinase B (Aur B), and Mps1 are involved at different control points in the cell cycle.
Fig 1. A diagram showing cell cycle progression and DNA repair. Image credit: Tocris Bioscience
During S-phase, DNA replication takes place in five stages. They are: initiation, unwinding, primer synthesis, elongation, and termination. Helicase enzymes “unwind” the DNA double helix, and telomerases decrease the ensuing torsional strain, making the single strands exposed and initiating the replication fork. The lagging strand of DNA is produced by Pol δ and the leading strand of DNA is produced by Pol ε. For both DNA polymerase ε and δ, PCNA is a cofactor and acts as a DNA clamp, which is significant in DNA synthesis as well as DNA repair. At the end of the termination phase, a phosphodiester bond is formed by DNA ligases, connecting the DNA strands together and forming new double-stranded DNA.
Fig 2. A diagram demonstrating DNA Replication. Image credit: Tocris Bioscience
Targeting Cancer Cells
Replicative stress can be enhanced by targeting critical DNA replication checkpoints and replication machinery, as well as by depleting nucleotides, thereby promoting fork collapse and fork stalling, which causes mitotic catastrophe and death in cancer cells.
Fig 3. A diagram showing the targeting of cancer cells. Image credit: Tocris Bioscience
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About Tocris Bioscience
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