Academic journal article Genetics

Molecular Genetic Analysis of Suppressor 2 of Zeste Identifies Key Functional Domains

Academic journal article Genetics

Molecular Genetic Analysis of Suppressor 2 of Zeste Identifies Key Functional Domains

Article excerpt

ABSTRACT

The Su(z)2 complex contains Posterior sex combs (Psc) and Suppressor 2 of zeste [Su(z)2], two paralogous genes that likely arose by gene duplication. Psc encodes a Polycomb group protein that functions as a central component of the PRC1 complex, which maintains transcriptional repression of a wide array of genes. Although much is known about Psc, very little is known about Su(z)2, the analysis of which has been hampered by a dearth of alleles. We have generated new alleles of Su(z)2 and analyzed them at the genetic and molecular levels. Some of these alleles display negative complementation in that they cause lethality when heterozygous with the gain-of-function Su(z)2^sup 1^ allele but are hemizygous and, in some cases, homozygous viable. Interestingly, alleles of this class identify protein domains within Su(z)2 that are highly conserved in Psc and the mammalian Bmi-1 and Mel-18 proteins. We also find several domains of intrinsic disorder in the C-terminal regions of both Psc and Su(z)2 and suggest that these domains may contribute to the essential functions of both proteins.

THE Su(z)2 complex of Drosophila spans 100 kb and contains two divergently transcribed genes, Posterior sex combs (Psc) and Suppressor 2 of zeste [Su(z)2] (Adler et al. 1989; Wu et al. 1989; Wu and Howe 1995). Of the two, Su(z)2 is the lesser known. It stands in stark contrast to Psc, which has been the focus of extensive genetic, molecular, and biochemical analyses for many years. Psc is a member of the Polycomb group (PcG) of genes, many of which function at the level of chromatin as part of at least two PcG repressive complexes, called PRC1 and PRC2 (reviewed by Brock and Fisher 2005; Breiling et al. 2007; Schuettengruber et al. 2007; Schwartz and Pirrotta 2007, 2008; Mateos- Langerak and Cavalli 2008). PRC2 contains the Enhancer of zeste [E(z)] protein, which provides a histone methyltransferase activity that methylates histone H3 on lysine 27 (reviewed by Cao and Zhang 2004). This epigenetic chromatin mark is believed to recruit PRC1 (Fischle et al. 2003; Min et al. 2003; but see also Kahn et al. 2006), which then functions to maintain target gene silencing. PRC1 contains .15 subunits (Saurin et al. 2001) and blocks both transcription and chromatin remodeling in vitro (Shao et al. 1999). These inhibitory activities can be reproduced by a minimal complex, called the PRC1 core complex (PCC), consisting of four proteins, including Psc, Polycomb (Pc), Polyhomeotic (Ph), and Sex combs extra (Sce) (Francis et al. 2001; Sce is also known as dRing1; Fritsch et al. 2003; Gorfinkiel et al. 2004). Psc can reproduce the inhibitory activities by itself, suggesting that it is a central component of PCC (Francis et al. 2001).

Many lines of evidence suggest that Su(z)2 is functionally related to, and even partially redundant with, Psc. For example, overexpression of either gene leads to bristle defects (Brunk et al. 1991b; Sharp et al. 1994;Wu and Howe 1995) and, as detailed below, certain alleles of either gene can act as suppressors or enhancers of an allele of the zeste (z) gene (Wu and Howe 1995). In addition, embryos homozygous for a deficiency that removes both genes, Su(z)21.b8, display cuticle defects that are more severe than those of embryos lacking either Psc or Su(z)2 alone (Adler et al. 1991; Soto et al. 1995; Wu and Howe 1995). Similarly, somatic clones homozygous for Su(z)21.b8 in wing imaginal discs show derepression of homeotic genes and cellular overgrowth, whereas clones homozygous for loss-of-function (l-o-f) alleles of either Psc or Su(z)2 do not (Beuchle et al. 2001). Su(z)2 also colocalizes with Psc and Pc at many sites on polytene chromosomes (Rastelli et al. 1993; Platero et al. 1996; Sharp et al. 1997) and, very recently, co-immunoprecipitation experiments using Drosophila and cell-line extracts suggest that Su(z)2 exits in a complex that also contains Pc, Ph, and Sce/ dRing1, which are the three non-Psc members of PCC (Lo et al. …

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