The role of the Mis18α-β complex and its interactions with HJURP and CENP-A in human centromeric chromatin establishment

Nardi, Isaac, Biochemistry and Molecular Genetics - Graduate School of Arts and Sciences, University of Virginia
Foltz, Daniel, Biochemistry, University of Virginia

The centromere, in higher eukaryotes, is an epigenetically specified locus that is the site kinetochore formation on each chromosome during mitosis. The epigenetic mark that defines a centromere as of this writing is the histone H3 variant Centromere Protein-A (CENP-A). The establishment and maintenance of CENP-A at centromeres is absolutely critical for proper chromosome segregation and ploidy in cells. Several key factors have been identified as crucial machinery involved in CENP-A deposition. Understanding how a specific subset of these factors maintains CENP-A specifically at centromeric chromatin is the theme of this work. The second chapter of this work demonstrates the CENP-A chaperone HJURP is directly targeted to centromeres by the Mis18 complex. Furthermore, binding of Mis18 by HJURP mislocalizes the complex from centromeres giving cells control over where CENP-A deposition occurs and how much CENP-A gets consigned at centromeres. The third chapter characterizes a direct interaction between Mis18 and CENP-A that has never been characterized before. This work, though in its infancy, alludes to an important role of Mis18 as being an integral part of the CENP-A deposition machinery into centromeric chromatin. The fourth chapter describes the CENP-T/W/S/X complex and its ability to form “nucleosome-like” structures that may be involved in further differentiating the centromeres from outside chromatin. I also go over a potential role of HJURP in the DNA damage response which was touched on several years ago but not fully followed up ever since HJURPs role in CENP-A deposition has been discovered.

PHD (Doctor of Philosophy)
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