Cell cycle progression requires repression by Groucho during S-phase and its relief at G2-phase

Abstract

The cell cycle depends on a sequence of steps that are triggered and terminated via the synthesis and degradation of phase-specific transcripts and proteins. While much is known about how stage-specific transcription is activated, less is understood about how inappropriate gene expression is suppressed. In this paper we demonstrate that Groucho, the Drosophila orthologue of TLE1 and other related human transcriptional corepressors, regulates cell cycle progression in vivo. We show that although Groucho is expressed throughout the cell cycle, its activity is selectively inactivated by phosphorylation, except during S-phase when it represses e2f1 expression. Misregulated Groucho activity causes cell cycle arrest; in particular, both constitutive Groucho activity and failure to repress e2f1 cause cell cycle arrest phenotypes. We also show that the Cdk1 kinase is responsible for stage-specific phosphorylation of Groucho in vivo. We propose that Groucho and its orthologues play key roles in the metazoan cell cycle that may explain the links between TLE corepressors and several types of human cancer.