Tuesday, 10 December 2013

The Spindle Assembly Checkpoint Mechanism and the Consequences of its Dysfunction

Mitotic division (“M phase”) is the culmination of the eukaryotic cell cycle for somatic cells. Mitotic cell division is divided into six phases. The first is prophase, which is characterized by chromosome condensation (the reorganization of the sister chromatids into compact rod-like structures). Following condensation, assembly of the mitotic spindle apparatus occurs outside the nucleus between the two centrosomes which have duplicated and moved apart to the poles of the cell.

The second stage of mitosis is prometaphase, which is marked by the disintegration of the nuclear envelope. This is followed by metaphase, where sister chromatids are attached to opposite spindle poles by microtubules bound to protein complexes called kinetochores. In animal cells, 10-40 microtubule-binding sites are associated with any one kinetochore. In yeast, each kinetochore contains only one attachment site. At this point, the chromosomes are seen to be aligned at the cell’s equator (the metaphase plate). The sister chromatids are themselves held together by the protein cohesin.

At anaphase, the sister chromatids separate to form two daughter chromosomes that are pulled towards opposite poles of the spindle. Microtubules bound to kinetochores, as well as the centrosome, are reeled in towards the cell’s periphery by specialized dynein motor proteins that ‘walk’ towards the minus end of the microtubule but are held stationary by cargo-binding domains that are anchored to the cell cortex.

The next phase in the cycle is telophase, the stage at which the daughter chromosomes de-condense at the spindle poles and a new nuclear envelope is assembled. A contractile ring is then formed, marking the final stage of the process -- cytokinesis. The contractile ring is comprised of actin and myosin filaments. The cell thus differentiates to form two new daughter cells, each with a nucleus containing a complete and identical set of chromosomes.