Research Article

Protein phosphatase 2A contributes to separase regulation and the co-ordination of anaphase

Christopher P. Wardlaw

University of Manchester, Michael Smith Buliding, Oxford Road, Manchester, M13 9PT, UK

Received:

18 Oct 2009

Accepted:

29 Jan 2010

Published:

13 Feb 2010

Volume:

3

Issue:

1

Keywords:

prophase, anaphase, chromatid, cohesin, separase, Pp2A

Abstract:

This study explores the role of the phosphatase Pp2A in regulation of anaphase onset in human cells. During the mitotic cell cycle, cells replicate their DNA in S-phase giving sister chromatids. These chromatids remain tethered together by the cohesin ring until anaphase. The onset of anaphase is triggered by the activation of separase, a protease which cleaves the cohesin ring structure, thereby allowing the sister chromatids to be pulled to opposite ends of the spindle. Prior to anaphase, separase is held in check by one of two inhibitors, namely securin or cyclin B1. Recently, it has been shown that securin-bound separase also binds the protein phosphatase, Pp2A. Importantly, the binding of Pp2A is regulated by separase autocleavage; upon activation, separase autocleaves and releases Pp2A. Strikingly, expression of a non-cleavable separase induces premature sister chromatid separation. Here, we show that the ability of non-cleavable separase to prematurely induce chromatid disjunction requires its catalytic activity. These data lend weight to a handover model whereby separase is initially inhibited by securin; then as securin is degraded, separase autocleaves, Pp2A is released thereby allowing cyclin B1 binding; this in turn maintains separase inhibition until cyclin B1 is degraded. One exciting extension of this model is that the release of Pp2A provides a burst of phosphatase activity just prior to chromatid separation, perhaps to ‘forewarn’ the cell that anaphase onset is imminent. For example, Pp2A activation may ensure that kinetochore–microtubule interactions are stabilized to ensure that all the chromatids are locked onto their K-fibres at the point when sister chromatid cohesion is lost. This study has important implications in understanding how defects in separase regulation can lead to aneuploidy and diseases such as cancer.

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