Checkpoint Metaphase-anaphase

The metaphase-anaphase checkpoint controls the formation of the spindle apparatus and the correct alignment of chromosomes, and may initiate metaphase arrest (see Chapter 13). On failure of the control system, the occmrence of abnormal chromosomes is favored. In various cancer cells, chromosomal instabUity is associated with loss of function of the BUBl gene, which is part of the metaphase-anaphase checkpoint (Cahill et al., 1998). 

Other important cell cycle transitions are entry into S phase and the G2/M transition. At the G2/M transition, it is registered whether S phase has been completely executed, and the integrity of the DNA is examined at a DNA damage checkpoint. There are other important cell cycle transitions in M phase between metaphase and anaphase. At this point, an important and irreversible decision is made for progress of mitosis if the spindle apparatus is correctly formed and the sister chromatids are correctly aligned, the cell cycle may proceed. 

Destruction of cohesin allows the spindle microtubules to pull the separated chromatids to opposite poles of the cell. Failure of spindle attachment to a single kinetochore activates the SAC (spindle assembly checkpoint), which arrests cells at metaphase until corrections are effected and equal distribution of chromosomes has been ensured. A sensory mechanism initiates the wait anaphase signal from an imattached kinetochore and triggers the accu mulation of the checkpoint components that comprise the Bub (budding uninhibited by benomyl)-Mad (mitotic arrest deficient) families of proteins. 

Another class of substrates comprises the anaphase inhibitors, e. g., the protein securin. Securin is an inhibitor of a protease named separase, which cleaves proteins responsible for sister chromatid cohesion in metaphase. Destruction of these inhibitors is necessary for triggering of sister chromatid separation and progression into anaphase. Because of its central function, the APC is part of several cell cycle checkpoints, e. g., a DNA damage checkpoint and the mitotic spindle checkpoint. 

Cells with abnormal numbers of chromosomes form when certain cell-cycle checkpoints are nonfunctional. As discussed in Chapter 21, the unreplicated-DNA checkpoint normally prevents entry into mitosis unless all chromosomes have completely replicated their DNA the spindle-assembly checkpoint prevents entry into anaphase unless all the replicated chromosomes attach properly to the metaphase mitotic apparatus and the chromosome-segregation checkpoint prevents exit from mitosis and cytokinesis if the chromosomes segregate improperly (see Figure 21-32, steps [H- 3D. As advances are made in Identifying the proteins that detect these abnormalities and mediate cell-cycle arrest, the molecular basis for the functional defects leading to aneuploidy in tumor cells will become clearer. 

The analysis of the distribution of both enzymes further in the cell cycle indicates a brief association of PARP-2 with the outer kinetochore at centromeres (inset panel G). In contrast to PARP-1 that stays on condensed chromatin during the next stages, i.e., metaphase and early anaphase (panels C and D), PARP-2 relocates to the spindle (panel H) and to the spindle midzone (panel 1) and finally to the midbody (panel J) during cytokinesis. The dynamic association of PARP-2 with centromeres is therefore more akin to the previously described checkpoint proteins involved in spindle assembly. In line with this idea, the enhanced binding of PARP-2 to centromeres is observed when loss of spindle tension is induced by colcemid or taxol. ... 

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