Chromosome segregation: centromeric chromatin and kinetochore assembly

 

     The process of chromosome segregation is highly conserved. An essential chromosomal element is the centromere which, with its associated kinetochore (a multi-component protein complex), captures spindle microtubles and separates chromosomes to daughter nuclei by movement along microtubules to spindle poles. Defective kinetochore function leads to elevated rates of chromosome loss and gain. The generation of such aneuploid cells represents the most common form of chromosome abnormality in man contributing to a high incidence of spontaneous abortion and genetic disease. The overall aim of our research is to increase understanding of centromere structure and function by using fission yeast, Schizosaccharomyces pombe, as a model organism. The insights gained can then be applied to human conditions that arise due to defective chromosome segregation.
The fission yeast is our organism of choice. Its centromeres are relatively complex, for example, their repetitive nature is reminiscent of the large repetitive arrays associated with of most higher eukaryotic centromeres. We have established that as in fruit fly, mouse and human cells these regions are "heterochromatic" in fission yeast. Thus when marker genes are placed within these centromeres they are inactivated. We have used this "gene silencing" to identify proteins involved in centromere function. Several of these proteins are components of, or, are required for the formation of this specialised silent chromatin which contributes to centromere function and thus the process of chromosome segregation. Recently we have demonstrated that one function for heterochromatin at centromeres is to attract a high concentration of the cohesin glue to hold sister-centromeres together until they segregate to daughter cells. This explains the high frequency of lagging chromosomes seen on anapahse spindles in cells with defective centromeric heterochromatin.