Publication — IRIC

Targeting the INCENP IN-box-Aurora B interaction to inhibit CPC activity in vivo.

The chromosome passenger complex (CPC) is an essential regulator of mitosis and cytokinesis. The CPC consists of Aurora B kinase, inner centromere protein (INCENP), and the targeting subunits survivin and borealin/Dasra B. INCENP is a scaffolding subunit for the CPC and activates Aurora B via its conserved IN-box domain. We show that overexpression of soluble IN-box in HeLa cells affects endogenous CPC localization and produces a significant increase in multinucleated and micronucleated cells consistent with CPC loss of function. The dominant-negative effect of soluble IN-box expression depends on residues corresponding to hINCENP W845 and/or F881, suggesting that these are essential for Aurora B binding in vivo. We then screened a targeted library of small (five to nine residues long) circular peptide (CP) IN-box fragments generated using split intein circular ligation of proteins and peptides (SICLOPPS) methodology. We identified a number of CPs that caused modest but reproducible increases in rates of multinucleated and micronucleated cells. Our results provide proof of concept that inhibition of the Aurora B-IN-box interaction is a viable strategy for interfering with CPC function in vivo.

Publication date
November 12, 2014
Principal Investigators
Gohard FH, St-Cyr DJ, Tyers M, Earnshaw WC
PubMed reference
Open Biol 2014;4(11)
PubMed ID
25392451
Affiliation
Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Michael Swann Building, Kings Buildings, Mayfield Road, Edinburgh EH9 3JR, UK.