Differential Binding Partners of the Mis18α/β YIPPEE Domains Regulate Mis18 Complex Recruitment to Centromeres

Abstract

The Mis18 complex specifies the site of new CENP-A nucleosome assembly by recruiting the CENP-A specific assembly factor HJURP (Holliday junction recognition protein). The human Mis18 complex consists of Mis18α, Mis18β and Mis18 binding protein 1 (Mis18BP1/hsKNL2). Although Mis18α and Mis18β are highly homologous proteins, we find that their conserved YIPPEE domains mediate distinct interactions that are essential to link new CENP-A deposition to existing centromeres. We find that Mis18α directly interacts with the N-terminus of Mis18BP1; whereas, Mis18β directly interacts with CENP-C during G1 phase, revealing that these proteins have evolved to serve distinct functions in centromeres of higher eukaryotes. The N-terminus of Mis18BP1, containing both the Mis18α and CENP-C binding domains, is necessary and sufficient for centromeric localization. Therefore, the Mis18 complex contains dual CENP-C recognition motifs that are combinatorially required to generate robust centromeric localization that leads to CENP-A deposition.

Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence

“…As such, AURKA is a hotly pursued in cancer therapy (Dominguez‐Brauer et al ., 2015; Plotnikova et al ., 2015). Additionally, OIP5 is also known as Mis18β which has recently been shown to play an important role in chromatid separation during mitosis (Nardi et al ., 2016; Stellfox et al ., 2016), adding another appealing feature for its inclusion in SigMuc1NW. Intriguingly, among the 15 genes, only four are known to function in PC and all four genes facilitate CRPC development, which is in accordance with the detection of SigMuc1NW elevation in mCRPCs (Table 6).…”

Posttranslational mechanisms controlling centromere function and assembly

“…The human Mis18 complex forms an oligomeric structure that includes Mis18α and Mis18β paralogs, and Mis18BP1 [51 •• ,52 •• ]. CENP-C has been shown to participate in recruiting the Mis18 complex proteins to the existing centromere; although, it is unclear whether this interaction fully accounts for Mis18 recruitment [53–55]. More recently, a direct interaction between Mis18BP1 and CENP-A has been identified in Xenopus and chickens [56,57].…”

CDK-regulated dimerization of M18BP1 on a Mis18 hexamer is necessary for CENP-A loading

“…Vertebrate Mis18 complex consists of Mis18α and Mis18β, which are non-redundant and physically interacting paralogs, and M18BP1 (also known as KNL2) (Fujita et al, 2007). The Mis18 complex interacts with the CENP-A-specific chaperone HJURP (Dunleavy et al, 2009; Foltz et al, 2009; Nardi et al, 2016; Wang et al, 2014) and with CCAN subunits (Dambacher et al, 2012; Hori et al, 2013; Moree et al, 2011; Shono et al, 2015; Stellfox et al, 2016) (Figure 1A). Interactions of this machinery enable the recruitment of new CENP-A to already existing centromeres.

10.7554/eLife.23352.002Figure 1.CDK1 regulates binding of M18BP1 1-140 and Mis18α:Mis18β.( A ) Simplified current model of the cell-cycle-dependent assembly of the CENP-A deposition machinery.

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“…Recent studies of the single Schizosaccharomyces pombe Mis18 ortholog and of the human Mis18α:Mis18β complex suggested that Mis18 proteins form tetramers (Nardi et al, 2016; Subramanian et al, 2016). A segment of M18BP1 comprising ~380 N-terminal residues was shown to be responsible for a physical interaction with the Mis18α:Mis18β complex (Ohzeki et al, 2016; Stellfox et al, 2016). …”