Cell division is a heavily regulated multi-phase process that, ideally, replicates the genome and distributes it evenly between two daughter cells. Eukaryotic cells have evolved checkpoint pathways to ensure that cell division is stopped when conditions are detrimental.
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The primary G1/S cell cycle checkpoint regulates eukaryotic cells’ commitment to enter DNA synthesis (S phase) and serves as a stop/go decision prior to cell division.
Cyclin-dependent kinase complexes, Cyclin D-CDK4/6 and Cyclin E-CDK2, collaborate to relieve inhibition of a dynamic transcription complex that includes the retinoblastoma protein (Rb) and E2F.
Inhibitors of CDK4/6 are now used in conjunction with hormone therapies to treat some types of breast cancer and are being investigated for use in other cancer treatments.
The G2/M DNA damage checkpoint occurs after the S phase and stops a cell with genomic DNA damage from entering mitosis (M-phase). Cyclin B-cdc2 activity is critical for controlling the G2/M- phase transition.
DNA damage activates the sensory DNA-PK/ATM/ ATR kinases, which initiate two parallel cascades that eventually deactivate the Cyclin B-cdc2 complex. The first cascade quickly limits mitosis progression: the CHK1 and CHK2 kinases phosphorylate and deactivate cdc25, preventing cdc2 activation.
The second cascade results in the phosphorylation and activation of the tumor suppressor p53, which enhances the transcription of genes that cause apoptosis, cell cycle arrest, or senescence. MDM2 and MDM4 (MdmX) are crucial negative regulators of p53 stability and activity and are typically overexpressed in cancer.
Small molecules that interfere with the interaction of p53 with these inhibitors are presently being studied in preclinical trials for cancer therapies.
This free eBook from Cell Signaling Technology explores the cell cycle and DNA damage and repair in depth.
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