Stuxnet Facilitates the Degradation of Polycomb Protein during Development

Abstract

Polycomb-group (PcG) proteins function to ensure correct deployment of developmental programs by epigenetically repressing target gene expression. Despite the importance, few studies have been focused on the regulation of PcG activity itself. Here, we report a Drosophila gene, stuxnet (stx), that controls Pc protein stability. We find that heightened stx activity leads to homeotic transformation, reduced Pc activity, and de-repression of PcG targets. Conversely, stx mutants, which can be rescued by decreased Pc expression, display developmental defects resembling hyperactivation of Pc. Our biochemical analyses provide a mechanistic basis for the interaction between stx and Pc; Stx facilitates Pc degradation in the proteasome, independent of ubiquitin modification. Furthermore, this mode of regulation is conserved in vertebrates. Mouse stx promotes degradation of Cbx4, an orthologous Pc protein, in vertebrate cells and induces homeotic transformation in Drosophila. Our results highlight an evolutionarily conserved mechanism of regulated protein degradation on PcG homeostasis and epigenetic activity.

Stuxnet Recruits the Proteasome to Take Down Polycomb

“…In mammalian systems, for example, Pc-G gene activity is essential for stem cell maintenance and altered Pc-G activity is associated with tumorigenesis. Thus, the findings reported by Du et al (2016) may have important implications well beyond the fly system. Indeed, the authors mention the finding of stx dysregulation and stx mutations in certain forms of cancer.…”

“…In this issue of Developmental Cell, Du et al (2016) describe a gene named stuxnet that regulates Polycomb protein stability, thereby influencing the activity of the Polycomb-group repressive chromatin complexes.…”

“…A great deal of literature exists about the composition of the two major Pc-G repressive complexes, PRC1 and PRC2, the epigenetic modifications they impose on the associated chromatin, and how they are recruited to their targets. In a nice blend of genetic and molecular approaches in Drosophila, Du et al (2016) describe in this issue of Developmental Cell an additional layer of Pc-G regulation that acts by altering the stability of the Polycomb protein (Pc) itself.…”

“…Using a collection of transposons engineered to induce transcription of the DNA surrounding their site of insertion in Drosophila, Du et al (2016) performed a ''mis-expression'' screen for developmental genes located on the X chromosome. Using this approach, they identified a gene that affects antennal development, which turns out, as described below, to regulate the stability of the Pc protein itself.…”

Stuxnet detected, Pc breaks down

“…Furthermore, PcG protein stability as well as their localization or enzymatic activities has also been reported to be regulated by post-translational modifications (PTMs), such as phosphorylation and ubiquitination (Niessen et al, 2009). In a recent issue of Developmental Cell, Du et al described an additional layer of PTM-independent regulation on PcG (Pc) stability (Du et al, 2016) (Figure 1).…”