Spindle assembly checkpoint

A signal transduction pathway required for proper chromosome alignment during mitosis. The spindle assembly checkpoint is activated during mitosis in response to the presence of chromosomes that are not attached to spindle microtubules or that are not properly aligned at the metaphase plate. The spindle checkpoint... 

The duration of the M phase is largely determined by the time necessary for the formation of a functional metaphase spindle and the correct alignment of all chromosomes in the metaphase plate. The spindle assembly checkpoint prevents the exit from the M phase before the proper alignment of all chromosomes into a metaphase plate in many cell types. This kind of control is already operational... 

The cell cycle contains built-in control mechanisms that register defects in the course of the cell cycle and bring about a halt in the cell cycle to enable the fault to be repaired or to lead the cell to programmed cell death. These control mechanisms are also known as checkpoints. These are biochemical pathways that are activated when a fault occurs and can influence other critical steps of the cell cycle. Of particular importance for the cell cycle is the DNA damage checkpoint. Another important checkpoint is the spindle assembly checkpoint, which is not well biochemically characterized, however. 

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. 

The spindle assembly checkpoint induced by paclitaxel is partially impaired when BRCAl expression is repressed in MCF-7 cells. BRCAl up-regulates BubRl transcription, and BubRl transcription and expression are significantly down-regulated in MCF-7... 

Mondal G, Baral RN, Roychoudhury S. A new Mad2-interacting domain of Cdc20 is critical for the function of Mad2-Cdc20 complex in the spindle assembly checkpoint. BiochemJ2006-,396 243-253. 

Weitzel DH, Vandre DD. Differential spindle assembly checkpoint response in human lung adenocarcinoma cells. Cell Tissue Res 2000 300 57-65. 

Anand S, Penrhyn-Lowe S, Venkitaraman AR. AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell 2003 3 51-62. 

Sudo T, Nitta M, Saya H et al. Dependence of paclitaxel sensitivity on a functional spindle assembly checkpoint. Cancer Res 2004 64 2502-2508. 

Jablonski SA, Chan GK, Cooke CA, Eamshaw WC, Yen TJ. The hBUBl and hBUBRl kinases sequentially assemble onto kinetochores during prophase with hBUBRl concentrating at the kinetochore plates in mitosis. Chromosoma 1998 107 386-396. Zhou J, Yao J, Joshi HC. Attachment and tension in the spindle assembly checkpoint. J. Cell. Sci. 2002 115 3547-3555. 

Rieder CL, Maiato H. Stuck in division or passing through what happens when cells cannot satisfy the spindle assembly checkpoint. Dev. Cell. 2004 7 637-651. 

Chen RH, Waters JC, Salmon ED, Murray AW. Association of spindle assembly checkpoint component XMAD2 with unattached kinetochores. Science 1996 274 242-246. 

Larsen N, Harrison S. Crystal structure of the spindle assembly checkpoint protein Bub3. J Mol Biol 2004 344(4) 885-892. 

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). 

Shah, J. V., and D. W. Cleveland. 2000. Waiting for anaphase Mad2 and the spindle assembly checkpoint. Cell 103 997-1000. 

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. 

Explain the concept of loss of heterozygosity (LOH). Why do most cancer cells exhibit LOH of one or more genes How does failure of the spindle assembly checkpoint lead to loss of heterozygosity ... 

If a cell enters mitosis without DNA damage another major checkpoint operates during M phase to ensure that chromosomes are properly segregated. This spindle assembly checkpoint (SAC) keeps cells in mitosis until all chromosomes have acquired a bipolar attachment to the spindle. The process of bipolar attachment starts in pro-metaphase, usually with the attachment of a single kinetochore on a sister chromatid to microtubules emanating from a single spindle pole. This monotelic attachment persists until the unattached kinetochore is captured by microtubules from the opposite spindle pole (amphitelic... 

Figure 17.6 Attachment of kinetochores to the spindle. During prometaphase, kinetochores on chromosomes capture microtubules emanating from the spindle poles. Several types of attachments are possible, however only amphitelic (i.e., bipolar) attachment is compatible with segregation of chromosomes to opposite poles when anaphase begins. Monotelic and syntelic attachments trigger the spindle assembly checkpoint to give more time for them to be converted to amphitelic attachments. Merotelic attachments do not trigger the spindle assembly checkpoint but are corrected by a mechanism that requires Aurora B kinase.

Explain how the spindle assembly checkpoint ensures that chromosomes are equally segregated during mitosis. 

Hauf, S., Cole, R W., LaTerra, S., Zimmer, C., Schnapp, G., Walter, R, et al. (2003). The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. The Journal of CeU Biology, 161, 281-294. 

---