G2-M Phase Transition
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G2-M Phase Transition
The cellular responses to DNA damage induced by ionizing radiation include activation of cell cycle checkpoints that delay progression of cells through the cell cycle. Ionizing radiation-induced checkpoints are active at the transition from the G1-phase to the S-phase, in the S-phase, and at the transition from the G2-phase to mitosis (G2/M). The surveillance mechanisms responsible for initiating these checkpoints appear to facilitate maintenance of the integrity of the genome, presumably because they ensure that damaged DNA templates are neither replicated nor segregated into the daughter cells until they are repaired. The option to undergo apoptosis can be considered as one of the checkpoint endpoints, and a failure of the cell to die under appropriate circumstances can lead to inappropriate survival of cells with altered genomes (Ref.1).

The final gatekeeper that blocks the entry of DNA-damaged cells into M-phase (Mitosis) is the G2 checkpoint (Ref.2). The G2/M DNA damage checkpoint prevents the cell from entering mitosis if the genome is damaged. The CDC2 (CDK1)-Cyclin-B kinase is pivotal in regulating this transition. The CDC2 kinase in its active form exists as a complex with Cyclin-B and together they form MPF (Mitosis Promoting Factor). The activity of MPF oscillates in the cell cycle and is triggering factor for entry of the cell into M-phase. It catalyzes the phosphorylation of Lamins and Histone-1, and is involved in the regulation of events receding cell division, such as spindle formation, chromatin condensation, and fragmentation of the nuclear envelope and of organelles such as the Golgi and ER (Endoplasmic Reticulum). DNA damage activates the DNA-PK/ATM (Ataxia Telangiectasia Mutated)/ATR (ATM and Rad 3-related) kinases that lead to the activation of p53, Chk1 and Chk2 (Ref.2). The Chks, in turn, phosphorylates the mitosis-promoting phosphatase, CDC25C. Phosphorylation of CDC25C creates a binding site for 14-3-3 proteins, and, in the 14-3-3-bound form, CDC25C is either catalytically inhibited or sequestered in the cytoplasm. In any case, the phosphorylated, 14-3-3-bound form of CDC25C is prohibited from dephosphorylating and activating the mitotic Cyclin-B-CDC2 kinase, and the damaged cells are effectively blocked from entering mitosis. Phosphorylation of p53 dissociates it from MDM2 (Mouse Double Minute-2), activating its DNA binding activity. The genes that are turned on by p53 include 14-3-3s, which binds to the phosphorylated Cyclin-B-CDC2 kinase and exports it from the nucleus; GADD45 (Growth Arrest and DNA Damage-inducible), which apparently binds to and dissociates the Cyclin-B-CDC2 kinase; and p21(CIP1), an inhibitor of a subset of the cyclin-dependent kinases including CDC2 (Ref.3). A crucial regulatory element of M-phase is the concentration of Cyclin-B. The concentration of Cyclin-B increases with the entry into S-phase to a threshold at which it is sufficient to trigger mitosis. The extent of phosphorylation and the activity of the CDC25 phosphatase are subject to both positive and negative control. Overall, this regulation system ensures a rapid increase in activity of MPF at the G2/M-phase transition.

The activation of CDC2 and possibly of other mitotic protein kinases is thought to be largely responsible for the structural reorganization of the cell during prophase and metaphase. These events, in particular chromosome condensation and spindle assembly, are essential prerequisites for the separation of sister chromatids in anaphase (Ref.4). Loss of cell cycle checkpoints provides a growth advantage for tumor cells, but paradoxically, it is also loss of a protective mechanism. Thus cells with dysfunctional checkpoints are also more sensitive to agents that would normally trigger a response from the defective checkpoint. Thus the identification of checkpoint genes, defining their normal functions and the cellular stresses to which they respond during cell cycle has important implications for the development of new anticancer treatments (Ref.5).