Posterior sexcombs and Suppressor two of zeste: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

Gene name - Posterior sexcombs and Suppressor two of zeste

Synonyms -

Cytological map position - 49E7-F2

Function - transcriptional silencing

Keywords - Polycomb group, oncogene

Symbol - Psc and Su(z)2

FlyBase ID: FBgn0005624 and FlyBase ID: FBgn0265623

Genetic map position - 2-67

Classification - zinc finger ring motif

Cellular location - nuclear

NCBI link: Psc Entrez Gene
NCBI link:Su(z)2: Entrez Gene
Psc orthologs: Biolitmine
Su(z)2 orthologs: Biolitmine
Recent literature
Nguyen, S. C., Yu, S., Oberlick, E. and Wu, C. T. (2016). An unexpected regulatory cascade governs a core function of the Drosophila PRC1 chromatin protein Su(z)2. Genetics [Epub ahead of print]. PubMed ID: 27881472
Polycomb group (PcG) proteins are major chromatin-bound factors that can read and modify chromatin states to maintain gene silencing throughout development. This study focused on a close homolog of the PcG protein Posterior sex combs in order to better understand how these proteins affect regulation. This homolog, called Suppressor 2 of zeste, or Su(z)2 is comprised of two regions: the N-terminal "homology region" (HR), which serves as a hub for protein interactions, and the C-terminal region (CTR), which is believed to harbor the core activity of compacting chromatin. This paper describes classical genetic studies to dissect the structure of Su(z)2 Surprisingly, it was found that the CTR is dispensable for viability. Furthermore, the core activity of Su(z)2 seems to reside in the HR instead of the CTR. Remarkably, the data also suggest a regulatory cascade between CTR and HR of Su(z)2, which, in turn, may help prioritize the myriad of PcG interactions that occur with the HR.
Kennerdell, J. R., Liu, N. and Bonini, N. M. (2018). MiR-34 inhibits polycomb repressive complex 2 to modulate chaperone expression and promote healthy brain aging. Nat Commun 9(1): 4188. PubMed ID: 30305625
Aging is a prominent risk factor for neurodegenerative disease. Defining gene expression mechanisms affecting healthy brain aging should lead to insight into genes that modulate susceptibility to disease. To define such mechanisms, analysis of miR-34 mutants have been pursued in Drosophila. The miR-34 mutant brain displays a gene expression profile of accelerated aging, and miR-34 upregulation is a potent suppressor of polyglutamine-induced neurodegeneration. Pcl and Su(z)12, two components of polycomb repressive complex 2, (PRC2), are targets of miR-34, with implications for age-associated processes. Because PRC2 confers the repressive H3K27me3 mark, it is hypothesized that miR-34 modulates PRC2 activity to relieve silencing of genes promoting healthful aging. Gene expression profiling of the brains of hypomorphic mutants in Enhancer of zeste (E(z)), the enzymatic methyltransferase component of PRC2, revealed a younger brain transcriptome profile and identified the small heat shock proteins as key genes reduced in expression with age.
Kang, J. J., Faubert, D., Boulais, J. and Francis, N. J. (2020). DNA Binding Reorganizes the Intrinsically Disordered C-Terminal Region of PSC in Drosophila PRC1. J Mol Biol. PubMed ID: 32628956
Polycomb Group proteins regulate gene expression by modifying chromatin. Polycomb Repressive Complex 1 (PRC1) has two activities: a ubiquitin ligase activity for histone H2A and a chromatin compacting activity. In Drosophila, the Posterior Sex Combs (PSC) subunit of PRC1 is central to both activities. The N-terminal of PSC assembles into PRC1, including partnering with dRING to form the ubiquitin ligase. The intrinsically disordered C-terminal region of PSC compacts chromatin and inhibits chromatin remodeling and transcription in vitro. Both regions of PSC are essential in vivo. Crosslinking identifies interactions between the C-terminal region of PSC and the core of PRC1, including between N and C-terminal regions of PSC. New contacts and overall more compacted PSC C-terminal region conformations are induced by DNA binding. Protein footprinting of accessible lysine residues reveals an extended, bipartite candidate DNA/chromatin binding surface in the C-terminal region of PSC. Our data suggest a model in which DNA (or chromatin) follows a long path on the flexible disordered region of PSC. Intramolecular interactions of PSC detected by crosslinking can bring the high-affinity DNA/chromatin binding region close to the core of PRC1 without disrupting the interface between the ubiquitin ligase and the nucleosome. This approach may be applicable to understanding the global organization of other large intrinsically disordered regions that bind nucleic acids.
Candia, N., Ibacache, A., Medina-Yanez, I., Olivares, G. H., Ramirez, M., Vega-Macaya, F., Couve, A., Sierralta, J. and Olguin, P. (2023). Identification of atlastin genetic modifiers in a model of hereditary spastic paraplegia in Drosophila. Hum Genet 142(8): 1303-1315. PubMed ID: 37368047
Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterized by progressive dysfunction of corticospinal motor neurons. Mutations in Atlastin1/Spg3, a small GTPase required for membrane fusion in the endoplasmic reticulum, are responsible for 10% of HSPs. Patients with the same Atlastin1/Spg3 mutation present high variability in age at onset and severity, suggesting a fundamental role of the environment and genetic background. This study used a Drosophila model of HSPs to identify genetic modifiers of decreased locomotion associated with atlastin knockdown in motor neurons. First, a screen was performed for genomic regions that modify the climbing performance or viability of flies expressing atl RNAi in motor neurons. 364 deficiencies spanning chromosomes two and three were tested; 35 enhancer and four suppressor regions of the climbing phenotype were found. Candidate genomic regions could also rescue atlastin effects at synapse morphology, suggesting a role in developing or maintaining the neuromuscular junction. Motor neuron-specific knockdown of 84 genes spanning candidate regions of the second chromosome identified 48 genes required for climbing behavior in motor neurons and 7 for viability, mapping to 11 modifier regions. atl was found to interact genetically with Su(z)2, a component of the Polycomb repressive complex 1, suggesting that epigenetic regulation plays a role in the variability of HSP-like phenotypes caused by atl alleles. These results identify new candidate genes and epigenetic regulation as a mechanism modifying neuronal atl pathogenic phenotypes, providing new targets for clinical studies.

Three genes form the Suppressor of zeste 2 complex: Posterior sex combs (Psc), Su(z)2 and Su(z)2(D). The first two are well characterized; both show homology to two mammalian proteins of much smaller size. The first, mammalian bmi-1, is activated by leukemia virus insertion while the second, Mel-18, is a transcriptional repressor and tumor suppressor. Each protein has a RING-finger motif, a variant of the zinc finger motif (Brunk, 1991b and Kanno, 1995).

PSC and SU(Z)2 can cause mis-expression of homeotic genes and participate in defining the boundary of expression of BX-C and ANTP-C genes. Ectopic expression of homeotics in Pc-G mutants seems to be due to factors that normally activate these genes in particular parasegments. Transcription factors in Pc-G mutants are able to gain access to the regulatory DNA that otherwise would be silenced (Simon, 1992).

Two levels of functional backup operate in Su(z)2 and Psc. The genes are expressed maternally and are functionally redundant. Mutation in either can produce minimal disruption in morphology. Thus each can substitute for the other and the level of maternal protein is high enough to supply most zygotic needs (Soto, 1995). SU(Z)2 and PSC proteins co-localize to and silence many of the same chromosomal loci acted upon by other Pc-G proteins, suggesting that Pc-G proteins function in a multi-protein complex to maintain gene silencing (Adler, 1993).

A complex, termed PRC1 (Polycomb repressive complex 1), has been purified that contains the products of the PcG genes Polycomb, Posterior sex combs, polyhomeotic, Sex combs on midleg, and several other proteins. Preincubation of PRC1 with nucleosomal arrays blocks the ability of these arrays to be remodeled by SWI/SNF (see Drosophila Brahma). Addition of PRC1 to arrays at the same time as SWI/SNF does not block remodeling. Thus, PRC1 and SWI/SNF might compete with each other for the nucleosomal template. Several different types of repressive complexes, including deacetylases, interact with histone tails. In contrast, PRC1 is active on nucleosomal arrays formed with tailless histones (Shao, 1999).

It is apparent from the composition of PRC1 that there must be other PcG complexes in addition to PRC1. PRC1 purified via either tagged PH or PSC contains Pc, Psc, Ph-p, Ph-d, and Scm, as well as several other proteins. PRC1 does not contain Pcl and E(z). Previous studies using immunoprecipitation, in vitro binding, and/or yeast two-hybrid analysis have shown that Pc, Psc, and Ph interact with each other, and that Scm interacts with Ph. E(z) and Esc have been shown to interact with each other by similar approaches, and E(z) separates from PRC1 during chromatography. Similarly, mammalian homologs of PcG can also be separated into roughly two complexes, one containing homologs to Pc, Psc, and Ph, and the other containing homologs to E(z) and Esc. Another argument that E(z) and Esc form a separate complex with a distinct function is based on the observation that homologs to these genes are found in the C. elegans genome, whereas homologs to Pc, Ph, or Psc are not. The activities of PRC1 suggest that it may be directly involved in creating the repressed state, and that it may require other complexes for targeting. Through screens for homeotic derepression, 14 PcG genes have been well characterized genetically. It is possible that a subset of these genes are required for direct repression, while other PcG proteins function in targeting, regulation of repression activity, or maintenance of the repressed state through mitosis. How PcG proteins are recruited to their targets is still unknown, but several proteins have been suggested as candidates for this function, such as Esc and E(z), and sequence-specific DNA-binding proteins Pho, Trithorax-like, Hunchback (Hb), and the Hb interacting protein dMi-2. PRC1 does not contain E(z) and Trithorax-like. Using antibodies against a region of human YY1 that is conserved in Pho, it was found that Pho is unlikely to be in PRC1; an antibody made specifically against Pho is needed to verify this result. Due to the lack of antibodies, whether PRC1 contains Esc, Hb, or dMi-2 was not tested (Shao, 1999 and references).

The proteins encoded by two groups of conserved genes, the Polycomb and trithorax groups, have been proposed to maintain, at the level of chromatin structure, the expression pattern of homeotic genes during Drosophila development. To identify new members of the trithorax group, a collection of deficiencies were screened for intergenic noncomplementation with a mutation in ash1, a trithorax group gene. Five of the noncomplementing deletions uncover genes previously classified as members of the Polycomb group. This evidence suggests that there are actually three groups of genes that maintain the expression pattern of homeotic genes during Drosophila development. The products of the third group appear to be required to maintain chromatin in both transcriptionally inactive and active states. Six of the noncomplementing deficiencies uncover previously unidentified trithorax group genes. One of these deficiencies removes 25D2-3 to 26B2-5. Within this region, there are two allelic, lethal, P-insertion mutations that identify one of these new trithorax group genes. The gene has been called little imaginal discs based on the phenotype of mutant larvae. The protein encoded by the little imaginal discs gene is the Drosophila homolog of human retinoblastoma binding protein 2 (Gilde, 2000).

When heterozygous, trithorax mutations cause either no transformations or an extremely low frequency of transformations of the third thoracic segment to the second segment. However, when homozygous, trithorax mutations cause transformations of the first and third thoracic segments to the second segment and anterior transformations of the abdominal segments. Other genes in which mutations cause similar phenotypes have been classified as members of the trithorax group. Trithorax group genes have been identified by several approaches. Two of the trithorax group genes, ash1 and ash2, were identified as pupal lethal mutations that disrupt imaginal disc development. Most of the other trithorax group genes were identified in a genetic screen for dominant suppressors of the adult phenotypes of dominant Polycomb or Antennapedia mutations. Like mutations in Polycomb group genes, mutations in trithorax group genes show intergenic noncomplementation, i.e., heterozygosis for recessive mutations in two different trithorax group genes can cause an adult mutant phenotype. The phenotype can include partial transformations of the first and third thoracic segments to the second thoracic segment and partial anterior transformations of the abdominal segments. The similar phenotypes of mutations in trithorax group genes and their intergenic noncomplementation has suggested that the products of these genes also act via multimeric protein complexes. Indeed, a 2-MD complex has been detected in embryos that contains the products of the trithorax group genes, brahma. However, this complex does not contain the products of the trithorax group gene ash1, which is in a different 2-MD complex, which also contains the product of the trithorax gene, nor does this complex contain the product of ash2, which is in a 0.5-MD complex. Taking advantage of the phenomenon of intergenic noncomplementation, a large fraction of the Drosophila genome was screened to look for new trithorax group genes. Females heterozygous for an ash1 mutation were crossed to males heterozygous for one of 133 deficiencies and the progeny doubly heterozygous for the ash1 mutation and the deficiency for homeotic transformations were examined. In this way regions of the genome with candidate trithorax group genes were identified (Gilde, 2000).

Six of the deficiencies uncovered genes that were previously classified in the Polycomb group. They were so classified, because they either enhanced the Polycomb mutant phenotype or caused a phenotype like Polycomb mutants. This result was quite unexpected because the antagonism between trithorax and Polycomb group genes suggested that loss of function of Polycomb group genes should suppress trithorax mutant phenotypes, while these deficiencies showed an enhancement of trithorax group mutant phenotypes. Nevertheless it is likely that the Polycomb group genes uncovered by these deficiencies are responsible for the observed intergenic noncomplementation with ash1RE418. It was thought possible that the observed intergenic noncomplementation is specific for ash1 mutations rather than general for mutations in trithorax group genes. This possibility was excluded for four of the five genes by showing that E(Pc)1, Psc1, Su(z)21, AsxXF23, Asx3, and Asx13 also show intergenic noncomplementation with trxb11 and/or brm2 and increase the penetrance of two different double mutants: ash1VF101 trxb11 and brm2 trxe2. It has also been reported that Asx mutations show intergenic noncomplementation with mutations in trithorax group genes. In some of these cases, the different mutant alleles tested give inconsistent results. For example, both ScmD1 and Scmm56 show intergenic noncomplementation with ash1VV183 and enhance the phenotype of the ash1VF101 trxb11 double mutant, whereas Scm302 does not enhance the phenotype of ash1VV183 and suppresses the phenotype of ash1VF101 trxb11. It is supposed that this difference is due to differences in the specific alterations of the Scm protein caused by these mutations (Gilde, 2000).

Until now the antagonism of function between the products of Polycomb group genes and trithorax group genes has been demonstrated unidirectionally by the suppression of Polycomb group mutant phenotypes by mutations in trithorax group genes. Advantage was taken of the intergenic noncomplementation of mutations in trithorax group genes to assay suppression of trithorax group mutant phenotypes by mutations in genes previously classified as Polycomb group genes. Among ash1VF101;trxb11 and brm2;trxe2 double heterozygotes, 52% and 35%, respectively, of adult flies express transformations of the third thoracic segment to the second thoracic segment. Most mutations in seven of the genes that have been classified as members of the Polycomb group (Polycomb, polyhomeotic, pleiohomeotic, Polycomb-like, multi sex combs, extra sex combs, and Super sex combs) suppress the penetrance of these transformations, in both of these double heterozygotes. Moreover, most mutations in these genes do not show intergenic noncomplementation with mutations in any of the three trithorax group genes that have been tested. It is suggested that these genes represent the Polycomb group defined here as genes in which loss-of-function mutations enhance the dominant phenotype caused by Polycomb mutations and suppress the phenotype caused by heterozygosity for double mutations in trithorax group genes such as ash1VF101;trxb11 and brm2;trxe2 (Gilde, 2000).

The zeste (z) gene encodes a transcription factor that binds DNA in a sequence-specific manner. The z1 mutation causes reduced white gene transcription. Mutations in three genes identified as dominant modifiers of the zeste-white interaction, Enhancer of zeste, Suppressor of zeste-2, and Sex comb on midleg, can also cause phenotypes like mutations in Polycomb group genes. Here it is shown that mutations in these three genes also behave as mutations in trithorax group genes: they show intergenic noncomplementation with mutations in trithorax group genes and/or increase the penetrance of ash1VF101;trxb11 and/or brm2;trxe2 heterozygotes. Moreover, mutations in three other genes identified as suppressors of the zeste-white interaction, Suppressor of zeste-4, Suppressor of zeste-6, and Suppressor of zeste-7, may show intergenic noncomplementation with mutations in trithorax group genes and/or increase the penetrance of ash1VF101;trxb11 heterozygotes. The biochemical mechanism by which mutations in these genes modify the zeste-white interaction is not known. However, it is thought to be significant that many of the genes identified as Suppressors of zeste behave as if they are both trithorax and Polycomb group genes; that Enhancer of Polycomb is a suppressor of zeste, and that sex combs extra is an enhancer of zeste (Gilde, 2000).

It is proposed that the six genes (previously classified as Polycomb group genes) belong in a distinct group; in these genes, loss-of-function or antimorphic mutations show intergenic noncomplementation with mutations in trithorax group genes and increase the penetrance caused by double heterozygosis of mutations in trithorax group genes. It is proposed that this group be called the ETP (Enhancers of trithorax and Polycomb mutations) group. Loss-of-function mutations in this group of genes not only enhance the dominant phenotype caused by Polycomb mutations, as do mutations in Polycomb group genes but they also enhance the phenotype caused by heterozygosity for double mutations in trithorax group genes, such as ash1VF101;trxb11 and brm2;trxe2, as do mutations in trithorax group genes (Gilde, 2000).

Mutations in many of the genes that have been classified in the ETP group lead to ectopic expression of homeotic genes in embryos. It has been inferred from such results that the normal function of the products of these genes is to repress transcription. However, a recent study of the consequences of mutations in one of these genes, Enhancer of zeste, demonstrated both ectopic expression and loss of expression of the same homeotic genes. That study was made possible by the availability of a strong temperature-sensitive allele. Without such alleles it would be very difficult to directly assay other members of the group for loss of homeotic gene expression. Nevertheless, the enhancement of the phenotype of mutations in both Polycomb and trithorax group genes by loss-of-function mutations in genes of the ETP group is interpreted as an indication that the products of these genes are required for both activation and repression of transcription. It has been proposed that the product of the zeste gene itself is also involved in both activation and repression of transcription. Little information is available on the biochemical mechanism of action of any of these genes. There is evidence of a multimeric protein complex containing the products of the Polycomb group genes, Polycomb and Polyhomeotic, and of three different complexes containing the products of the trithorax group genes, brahma, ash1, and ash2. One way of rationalizing how mutations in the ETP group of genes could behave as both Polycomb and trithorax group mutations would be to suggest that the products of the ETP genes are components of complexes required for both repression and activation. Perhaps they are responsible for the structure of these complexes or different protein variants encoded by these genes are components of different complexes. Although Polycomb and trithorax group genes were first identified in Drosophila, homologous genes exist in mammals. Until now, most interpretations of the functions of the products of such genes have been based on the idea that the products of Polycomb group genes repress gene transcription and the products of trithorax group genes activate gene transcription. The data presented here together with earlier data suggest that some of the genes previously classified as Polycomb group genes and at least some of the genes identified as suppressors or enhancers of zeste belong to a group of genes whose products play a role in both the repression and activation of gene transcription. These data will require new interpretations of the functions of such genes (Gilde, 2000).


The Su(z)2-C consists of at least three subregions called Psc (Posterior sex combs), Su(z)2 and Su(z)2D (Distal). Psc and Su(z)2 are transcribed in opposite directions 116 kb apart (Brunk, 1991a and Wu, 1995).

There is evidence for two PSC mRNAs and evidence for two PSC proteins, altered either in abundance or size in Psc mutants (Martin, 1993).

cDNA clone length - 6031 for Psc


Amino Acids - 1603 for PSC; 1365 for Su(z)2

Structural Domains

The predicted protein sequence of the Pc-G gene Posterior sex combs, and of the neighboring and related gene Suppressor two of zeste encode large proteins that contain a 200 amino-acid domain identical over 37.4% that is also conserved in the murine oncogene bmi-1. The common domain includes a RING-finger motif, a C3HC4 zinc finger. At the amino terminus of this domain is a cysteine-rich sequence that has been proposed as a novel type of zinc finger (Brunk, 1991b).

The ExPASy World Wide Web (WWW) molecular biology server of the Geneva University Hospital and the University of Geneva provides extensive documentation for theZinc finger, C3HC4 type (RING finger) signature.

Posterior sexcombs and Suppressor two of zeste: Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

date revised: 21 APR 97 

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