JADE1 and HBO1/KAT7 proteins in the cytokinesis of epithelial cells. The role of PHD zinc fingers.

Abstract

Members of the conserved subfamily, JADE1S and JADE1L isoforms, are expressed in epithelial cells, fibroblasts, and epithelial cell lining in vivo. JADE1 proteins interact with histone acetyl transferase HBO1 complex. The two consecutive PHD zinc fingers of JADE1 bind chromatin. We recently reported novel effects of JADE1S on cytokinesis progression. JADE1S depletion facilitated G2/M-to-G1 transition and increased polyploidy and aneuploidy. JADE1S over-expression arrested cells in late cytokinesis, an effect reversed by AURKB inhibitor. In late cytokinesis cells JADE1S protein localized to the midbody. Results suggested a JADE1S role in final abscission delay. Here we investigated the expression of JADE1 in the central spindle, interactions with HBO1, and the role of PHD fingers in late cytokinesis arrest. The midzone begins to assemble in anaphase and forms into a midbody in cytokinesis. The midbody structure connects two daughter cells and is thought to bear factors controlling the final abscission. We questioned whether, similar to established factors, JADE1S is targeted to the central spindle structures in anaphase. Indeed, in cells transitioning from mitosis to cytokinesis, JADE1S was sequentially targeted to early midzone, midbody flanking zone, and midbody. The step-wise increase of JADE1S expression in midzone and midbody of synchronously dividing cells suggested protein recruitment. The increase of late cytokinesis arrest caused by recombinant JADE1S correlated with increased expression in midbody. Spatial analysis of the members of the chromatin passenger complex, microtubule associated proteins, and centralspindlin, revealed transient co-localization with JADE1S and mapped JADE1S within the cytokinesis bridge. Deletion of the two PHD zinc fingers inactivated JADE1S ability to arrest cells in late cytokinesis but did not affect its midbody localization. Thus, PHD zinc fingers are required for JADE1S cytokinesis delay but not for midbody targeting. Recombinant HBO1 protein decreased the proportion of late cytokinesis cells, prevented late cytokinesis arrest by JADE1S as well as its midbody localization. Enzyme inactive HBO1 mutant recapitulated the wild type phenotype. The results demonstrate antagonistic relationship and suggest HBO1-mediated midbody dislocation of JADE1S. Our study supports the role of JADE1S in cytokinesis delay and implicates protein partners.