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BS, Rowan University, 2010
Thesis Advisor: Nancy Walworth, PHD
Friday, December 18, 2015
Chromosome segregation requires appropriate association between microtubules of the mitotic spindle with regions of chromosomes marked by centromere-specific histones that associate with protein complexes to form kinetochores, structures designed for dynamic association with the microtubules. The regional centromeres of the fission yeast Schizosaccharomyces pombe share features in common with regional centromeres of mammalian cells and, like all eukaryotic centromeres, are marked by the centromere-specific histone Cenp-A. Mutations in proteins that form the fission yeast kinetochore result in missegregation of chromosomes such that daughter cells emerge from mitosis with unequal segregation of DNA. We find that multiple copies of Msc1, a fission yeast homologue of the KDM5 family of proteins, can suppress the growth defect of several kinetochore mutants, including mis16 and mis18 mutants, as well as mis6, mis15 and mis17, which are components of the Constitutive Centromere Associated Network (CCAN). Deletion of msc1 exacerbates both their growth defect and chromosome missegregation phenotype. The C-terminal PHD domains of Msc1, previously shown to associate with a histone deacetylase activity, are necessary for Msc1 function when kinetochore mutants are compromised. We also demonstrate that in the absence of Msc1, the frequency of localization to the kinetochore of Mis16 and Mis15 is altered from wild-type cells. As we show here for msc1, others have shown that elevating cnp1 levels acts similarly to promote survival of the CCAN mutants. Interestingly, however, the rescue of mis15 and mis17 by cnp1 is independent of msc1. Thus, Msc1 appears to contribute to the chromatin environment at the centromere: the absence of Msc1 increases sensitivity of cells to perturbations in kinetochore function, while elevating Msc1 overcomes loss of function of critical components of the kinetochore and centromere.