Project title: Centromeric Chromatin Assembly in Fission Yeast
Summary: Genomic integrity is fundamental to the unperturbed propagation of genetic information through generations. Key to this is the ability to accurately segregate genomic DNA through every round of cell division. Centromeres are the specialised sites on eukaryotic chromosomes where kinetochores, that govern spindle microtubule attachment, assemble during cell division. Centromere dysfunction, and consequent kinetochore instability, can therefore cause mis-segregation of chromosomes resulting in aneuploidy and genome instability, which contribute to cancer progression.
A plethora of evidence suggests that DNA sequence is neither necessary nor sufficient for the establishment of a functional centromere. It has therefore been proposed that centromeres are epigenetically inherited. The centromere-specific histone H3 variant CENP-A (CENtromere Protein-A) likely serves as the epigenetic mark that specifies active centromeres. By replacing canonical histone H3 in centromeric chromatin, CENP-A confers a unique chromatin environment to centromeres.
This PhD project will uncover the molecular mechanisms that govern centromere specification and inheritance through the regulation of the chromatin state at centromeres, specifically by the highly conserved Mis18 complex. Previous studies have shown that Mis18 promotes CENP-A assembly at centromeres in an evolutionarily conserved manner (from fission yeast to humans). Recent work has identified novel components of the Mis18 complex in fission yeast (Eic1 & Eic2), that promote CENP-A assembly in concert with Mis18. During the course of this PhD project, I will dissect the molecular aspects of how the Mis18 complex, as a whole, regulates CENP-A chromatin integrity.