Dissecting JADE1 pathway in the Regulation of Cytokinesis

Abstract

Cell cycle regulation is important for normal proliferation of epithelial cells and epithelial tissue homeostasis. The dis‐regulation of the cell cycle progression is linked to genetic instability, aneuploidy, and apoptosis. Cytokinesis, the final stage of cell division, is responsible for the proper partitioning of duplicated chromatin and other cell content between two distinct daughter cells. We previously identified that JADE1 protein associates with chromatin and promotes acetylation of bulk histone H4 by functioning as an adapter and scaffold in the HBO1 complex, which is histone acetyl transferase (HAT) responsible for bulk histone H4 acetylation in vitro and in cultured cells. Our finding of cell cycle mediated JADE1S chromatin shuttling and phosphorylation suggested JADE1 function in cell cycle progression, specifically during G2/M to G1 progression.Objectiveto examine JADE1 role in the regulation of the cell cycle.Materials and methodscultured cell lines, cDNA transfection, transduction, RNA interference, FACS, western blot, fluorescent confocal microscopy.ResultsThe depletion of JADE1 in synchronized dividing cells increased rates of G2/M to G1 progression as evident from kinetics of G1 cell accumulation. Importantly, JADE1S depletion decreased proportion of cytokinetic cells and increased multinucleates, while JADE1 over‐expression increased cytokinetic proportion. Interestingly, endogenous JADE1 in late telophase was associated with midzone and in cytokinesis with midbody. Inhibition of key mitotic regulator Aurora B kinase with a drug released JADE1S' effects on cytokinesis. These data demonstrate role in cytokinesis and suggest role in abscission delay. Further, we investigated whether HAT HBO1 and unresolved chromatin are involved in JADE1 cytokinesis pathway. According to our results, HBO1 exerts antagonistic effects on JADE1 function by interfering with JADE1‐mediated cytokinesis arrest. Moreover, HBO1 over‐expression compromised midbody associations of JADE1 in early cytokinesis.ConclusionsJADE1 represents novel cytokinesis factor; HAT HBO1 interferes with JADE1 function in cytokinesis.Support or Funding InformationNIH RO1 DK087910, Mallory Fund (Boston Medical Center, Pathology)