Abstract
The centromere, a chromosomal locus that acts as a microtubule attachment site, is epigenetically specified by the enrichment of CENP‐A nucleosomes. Centromere maintenance during the cell cycle requires HJURP‐mediated CENP‐A deposition, a process regulated by the Mis18 complex (Mis18α/Mis18β/Mis18BP1). Spatial and temporal regulation of Mis18 complex assembly is crucial for its centromere association and function. Here, we provide the molecular basis for the assembly and regulation of the Mis18 complex. We show that the N‐terminal region of Mis18BP1 spanning amino acid residues 20–130 directly interacts with Mis18α/β to form the Mis18 complex. Within Mis18α/β, the Mis18α MeDiY domain can directly interact with Mis18BP1. Mis18α/β forms a hetero‐hexamer with 4 Mis18α and 2 Mis18β. However, only two copies of Mis18BP1 interact with Mis18α/β to form a hetero‐octameric assembly, highlighting the role of Mis18 oligomerization in limiting the number of Mis18BP1 within the Mis18 complex. Furthermore, we demonstrate the involvement of consensus Cdk1 phosphorylation sites on Mis18 complex assembly and thus provide a rationale for cell cycle‐regulated timing of Mis18 assembly and CENP‐A deposition.
Highlights
Equal and identical distribution of chromosomes to each daughter cell during cell division is essential for maintaining genome integrity
New CENP-A must be deposited in each cell cycle
Mis18 centromere association subsequently allows HJURP, a CENP-A-specific chaperone, to associate with centromeres resulting in CENP-A loading [18,19]
Summary
Equal and identical distribution of chromosomes to each daughter cell during cell division is essential for maintaining genome integrity. The timing of CENP-A deposition varies among species (G1—humans and G2—Schizosaccharomyces pombe); the molecular mechanisms by which it is achieved share considerable similarity [3,5,8,9,10,11,12,13] This process is initiated by the centromere targeting of the Mis complex (composed of Mis18a, Mis18b, and Mis18BP1) along with canonical histone chaperones, RbAp46/48 [14,15,16]. We identify two conserved consensus Cdk phosphorylation sites (T40 and S110) within Mis18BP120–130 and show that phospho-mimicking mutations of these residues disrupt Mis complex formation This explains the molecular basis for Cdk1-mediated timing of Mis assembly and CENP-A deposition
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