The Mis18 Complex: Integrating Temporal and Spatial Signals for Centromere Epigenetic Inheritance

With every cell cycle, a cell must faithfully replicate its genetic information and distribute the duplicated genome equally between each daughter cell or risk genomic instability and cell death. To facilitate this essential process, centromeres are chromosomal domains that couple the pulling forces of the mitotic spindle to each sister chromatid. Centromere identity is dictated by the presence of nucleosomes containing the histone H3 variant, centromere protein A (CENP-A). Following S phase, newly synthesized nucleosomes must be deposited into chromatin in order to compensate for the dilution that occurs during chromatin replication. However, human cells do not deposit newly synthesized CENP-A nucleosomes until immediately after mitotic exit, in G1. While centromere architecture varies across species, the deposition of CENP-A is controlled by a group of conserved proteins, which includes the CENP-A assembly factor, Holliday junction recognition protein (HJURP) and the Mis18 complex. The human Mis18 complex consists of Mis18α, Mis18β and Mis18 binding protein 1 (Mis18BP1). In this dissertation, I will describe several aspects of this highly conserved complex and its role in the temporal and spatial regulation of CENP-A deposition. Chapter one will contain a general introduction to centromere architecture and function. In chapter two, I will describe how the Mis18 complex couples cell cycle progression to HJURP-mediated CENP-A deposition. In chapter three, I will detail the specific interactions that dictate Mis18 complex formation and centromere recognition. Finally, chapter four will highlight new preliminary data that will drive future experimental explorations of additional mechanisms guiding Mis18 complex recruitment and function.