Checkpoints in Cell-Cycle Regulation
■ Checkpoint controls function to ensure that chromosomes are intact and that critical stages of the cell cycle are completed before the following stage is initiated.
■ The unreplicated-DNA checkpoint operates during S and G2 to prevent the activation of MPF before DNA synthesis is complete by inhibiting the activation of CDK1 by Cdc25C (see Figure 21-32, 1).
■ The spindle-assembly checkpoint, which prevents premature initiation of anaphase, utilizes Mad2 and other proteins to regulate the APC specificity factor Cdc20 that targets securin for polyubiquitination (see Figures 21-32, 2, and 21-19).
■ The chromosome-segregation checkpoint prevents telophase and cytokinesis until daughter chromosomes have been properly segregated, so that the daughter cell has a full set of chromosomes (see Figure 21-32, [3).
■ In the chromosome-segregation checkpoint, the small GTPase Tem1 controls the availability of Cdc14 phosphatase, which in turn activates the APC specificity factor Cdh1 that targets B-type cyclins for degradation, causing inactivation of MPF (see Figure 21-10).
■ The DNA-damage checkpoint arrests the cell cycle in response to DNA damage until the damage is repaired. Three types of tumor-suppressor proteins (ATM/ATR, Chk1/2, and p53) are critical to this checkpoint.
■ Activation of the ATM or ATR protein kinases in response to DNA damage due to UV light or ^-irradiation leads to arrest in G1 and the S phase via a pathway that leads to loss of Cdc25A phosphatase activity. A second pathway from activated ATM/R stabilizes p53, which stimulates expression of p21CIP. Subsequent inhibition of multiple CDK-cyclin complexes by p21CIP causes prolonged arrest in G1 and G2 (see Figure 21-32, |4a|-|4d|).
■ In response to extensive DNA damage, p53 also activates genes that induce apoptosis.
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