Licensing of Centromeric Chromatin Assembly through the Mis18α-Mis18β Heterotetramer

Abstract

SUMMARY Centromeres are specialized chromatin domains specified by the centromere-specific CENP-A nucleosome. The stable inheritance of vertebrate centromeres is an epigenetic process requiring deposition of new CENP-A nucleosomes by HJURP. We show HJURP is recruited to centromeres through a direct interaction between the HJURP centromere targeting domain and the Mis18α-β C-terminal coiled-coil domains. We demonstrate Mis18α and Mis18β form a heterotetramer through their C-terminal coiled-coil domains. Mis18α-β heterotetramer formation is required for Mis18BP1 binding and centromere recognition. S. pombe contains a single Mis18 isoform that forms a homotetramer, showing tetrameric Mis18 is conserved from fission yeast to humans. HJURP binding disrupts the Mis18α-β heterotetramer and removes Mis18α from centromeres. We propose stable binding of Mis18 to centromeres in telophase licenses them for CENP-A deposition. Binding of HJURP deposits CENP-A at centromeres and facilitates the removal of Mis18, restricting CENP-A deposition to a single event per cell cycle.

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 modifications of CENP-A: marks of distinction

“…Both PLK1 and CDK are the regulators of CENP-A assembly factor Mis18 complex. The Mis18 complex, that includes Mis18BP1, Mis18 α and Mis18 β , is localized to centromeres during late telophase and early G 1 and is required for HJURP recruitment and new CENP-A deposition (Barnhart et al 2011; Fujita et al 2007; Hayashi et al 2004; Nardi et al 2016; Wang et al 2014). PLK1 phosphorylates the Mis18 complex and promotes its centromere localization (McKinley and Cheeseman 2014).…”

Kinetochore assembly and function through the cell cycle

“…The actual deposition of CENP-A occurs through recognition of the Mis18 complex by the HJURP-CENP-A-H4 complex ( Fig. 2b) (Nardi et al 2016). In humans, the N-terminal region of HJURP specifically binds CENP-A (Shuaib et al 2010;Hu et al 2011;Bassett et al 2012).…”

“…The interaction is sufficient for CENP-A deposition, when artificially tethered to ectopic noncentromeric regions (Barnhart et al 2011;Hori et al 2013). The C-terminal region of HJURP interacts with the Mis18α-β heterotetramer for its centromere recognition (Wang et al 2014;Perpelescu et al 2015;Nardi et al 2016). The Mis18α-β heterotetramer is disrupted immediately after binding to HJURP in centromeric chromatin, which limits continuous CENP-A deposition (Nardi et al 2016).…”

“…The C-terminal region of HJURP interacts with the Mis18α-β heterotetramer for its centromere recognition (Wang et al 2014;Perpelescu et al 2015;Nardi et al 2016). The Mis18α-β heterotetramer is disrupted immediately after binding to HJURP in centromeric chromatin, which limits continuous CENP-A deposition (Nardi et al 2016). Studies in Mis18 knockout mice revealed that the Mis18 complex alters the centromere chromatin by recruitment of DNA methyltransferase and histone acetyltransferase (Kim et al 2012).…”