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

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.