Regulation of the Cell Cycle-Checkpoints

27 May

In addition to the various components of the cell cycle and their regulation, the existence of sur- veillance systems that interrupt cell cycle progression when damage to the genome or spindle is detected or when cells have failed to complete an event has been described. These systems have been termed checkpoints (cf. Paulovich et al., 1997). The first checkpoint occurs in the region of the G1/S boundary in the cell cycle, as noted in Figure 9.5. Functioning of this checkpoint is seen when DNA strand breaks induce G1 arrest, thereby delaying the transition of cells from the G1 phase to the S phase. Other types of DNA damage that may cause a G1 arrest and function of the G1/S checkpoint include mutations, DNA adducts, replicative gaps, etc. (Kaufmann and Paules, 1996). A major function of the G1  arrest at this checkpoint is to allow DNA repair, primarily excisional repair, to function, thereby permitting the cell to continue through the cycle. One of the major mechanisms of the arrest is mediated by the p53 tumor suppressor gene that is acti- vated by DNA damage.  The enhanced  expression  of p53 allows for transactivation  of other genes, paramount among which is the Waf1 or p21 gene, which we have noted as a general in- hibitor of cyclin/CDK complexes. By this mechanism, the G1 checkpoint can be activated and will continue to be activated until repair has occurred, p53 activation is eliminated, and p21 is destroyed by proteolysis, allowing the cycle to continue. However, if the damage is irreparable or too severe, p53 activation may enhance and initiate the process of apoptosis, thus eliminating a cell whose DNA alterations could not be repaired. The reader should also note that the alter- ations inducing the activation of the G1 checkpoint are those we have already discussed as occur- ring during the process of initiation in carcinogenesis.  Thus, if DNA repair is faulty or a cell carrying a mutation gets through the checkpoint, initiation is a potential result. Another potential checkpoint is that of S-phase replicon initiation (Kaufmann and Paules, 1996).

Evidence for its existence comes from the fact that both chemical and physical damage to DNA that manages to escape the G1/S checkpoint may lead to an inhibition of replicon initiation of DNA synthesis during the S period. It is not completely clear which genes are involved in this process, but it is likely that ε, one of the DNA polymerases, as well as the ataxia telangiectasia (AT) gene (Chap- ter 5), is active in this process. The other major checkpoint is that of the G2/M boundary, which is activated by double-stranded DNA breaks and results in preventing the progression of the cy- cle through mitosis (Paulovich et al., 1997). This delay has been associated with an inhibition of the activity  of CDK1, which is associated  with cyclins A and B (cf. Kaufmann  and Paules,1996). Since repair of double-stranded DNA breaks is more complicated than that of simple ex- cisional repair (Chapter 3), delay at the G2/M checkpoint facilitates repair by increasing the time for repair to occur and by transcriptionally inducing gene expression concomitant with the inhi- bition of the activity of CDK1. An increase in the level of expression of cyclins A and B and of CDK1 occurs to compensate for the inhibition, possibly owing to phosphatase activity. However, if cells with unrepaired chromatin damage are driven into mitosis, the chance for major chromo- somal abnormalities  is great. Thus, failure of this checkpoint can lead to the induction of the stage of progression. A checkpoint at the spindle assembly has also been reported to occur in lower eukaryotes and quite probably occurs in mammals as well (Elledge, 1996).

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