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PubMed1995

Functional domains of the Escherichia coli ferric uptake regulator protein (Fur).

The functions of N- and C-terminal domains of the Fur repressor of Escherichia coli in promoter recognition and dimerization were studied. We investigated the ability of fusion proteins containing the N- or C-terminal domain of Fur to dimerize and to repress a Fur-regulated lacZ fusion gene. The N-terminal domain, when fused to the C-terminal domain of the repressor CI857, repressed a Fur-regulated lacZ fusion. However, the Fur-CI857 fusion was unable to complement the growth defect of an E. coli fur mutant on fumarate and succinate. The C-terminal domain of Fur, when fused to the N-terminus of CI857, repressed a lambda Pr-regulated lacZ fusion, indicating dimerization of the chimeric protein, which is a prerequisite for CI activity. Both fusion proteins were fully active under both iron-rich and iron-poor growth conditions. We conclude that the N-terminal domain of Fur is involved in recognition of the Fur-responsive promoter and the C-terminus mediates oligomerization of the repressor.

Bacterial Proteins↗
PubMed2003

Mechanism of SMRT corepressor recruitment by the BCL6 BTB domain.

BCL6 encodes a transcription factor that represses genes necessary for the terminal differentiation of lymphocytes within germinal centers, and the misregulated expression of this factor is strongly implicated in several types of B cell lymphoma. The homodimeric BTB domain of BCL6 (also known as the POZ domain) is required for the repression activity of the protein and interacts directly with the SMRT and N-CoR corepressors that are found within large multiprotein histone deacetylase-containing complexes. We have identified a 17 residue fragment from SMRT that binds to the BCL6 BTB domain, and determined the crystal structure of the complex to 2.2 A. Two SMRT fragments bind symmetrically to the BCL6 BTB homodimer and, in combination with biochemical and in vivo data, the structure provides insight into the basis of transcriptional repression by this critical B cell lymphoma protein.

Amino Acid Sequence↗
PubMed2001

Competence repression under oxygen limitation through the two-component MicAB signal-transducing system in Streptococcus pneumoniae and involvement of the PAS domain of MicB.

In Streptococcus pneumoniae, a fermentative aerotolerant and catalase-deficient human pathogen, oxidases with molecular oxygen as substrate are important for virulence and for competence. The signal-transducing two-component systems CiaRH and ComDE mediate the response to oxygen, culminating in competence. In this work we show that the two-component MicAB system, whose MicB kinase carries a PAS domain, is also involved in competence repression under oxygen limitation. Autophosphorylation of recombinant MicB and phosphotransfer to recombinant MicA have been demonstrated. Mutational analysis and in vitro assays showed that the C-terminal part of the protein and residue L100 in the N-terminal cap of its PAS domain are both crucial for autokinase activity in vitro. Although no insertion mutation in micA was obtained, expression of the mutated allele micA59DA did not change bacterial growth and overcame competence repression under microaerobiosis. This was related to a strong instability of MicA59DA-PO(4) in vitro. Thus, mutations which either reduced the stability of MicA-PO(4) or abolished kinase activity in MicB were related to competence derepression under microaerobiosis, suggesting that MicA-PO(4) is involved in competence repression when oxygen becomes limiting. The micAB genes are flanked by mutY and orfC. MutY is an adenine glycosylase involved in the repair of oxidized pyrimidines. OrfC shows the features of a metal binding protein. We did not obtain insertion mutation in orfC, suggesting its requirement for growth. It is proposed that MicAB, with its PAS motif, may belong to a set of functions important in the protection of the cell against oxidative stress, including the control of competence.

Amino Acid Sequence↗
PubMed2001

Functional cross-talk of HIV-1 Tat with p53 through its C-terminal domain.

Human immunodeficiency virus type 1 (HIV-1) Tat repressed the p53-dependent gene expression through its C-terminal domain of Tat (amino acid residues 73-86) independent of the involvement of NF-kappaB and coactivator CBP/p300. Although Tat did not directly bind to p53, this repression required the N-terminal domain of p53. In contrast, Tat and p53 cooperated in the activation of HIV-1 gene expression. Thus, the cross-talk between Tat and p53 may be linked with cellular transformation by HIV-1 infection or activation of HIV-1 replication.

Animals↗
PubMed2001

foxD5a, a Xenopus winged helix gene, maintains an immature neural ectoderm via transcriptional repression that is dependent on the C-terminal domain.

Xenopus foxD5a, the full-length fork head gene previously described as a PCR fragment (XFLIP), is first detectable at stage II of oogenesis. Low-abundance maternal transcripts are localized to the animal hemisphere of the cleavage embryo, and protein can be translocated to the nucleus prior to the onset of zygotic transcription. Zygotic expression is strongest in the presumptive neural ectoderm at gastrula and neural plate stages, but there is minor paraxial mesodermal expression during primary gastrulation that becomes significant in the tail bud during secondary gastrulation. Expression of foxD5a in animal cap explants induces elongation and expression of mesodermal, neural-inducing, and early neural-specifying genes, indicating a role in dorsal axis formation. Zygotic foxD5a expression is induced strongly by siamois, moderately by cerberus, weakly by Wnt8 and noggin, and not by chordin in animal cap explants. Expression of foxD5a in whole embryos has differential dorsal and ventral effects. Ventral mRNA injection induces partial secondary axes composed of expanded mesodermal and epidermal tissues, but does not induce ectopic neural tissues. Dorsal mRNA injection causes hypertrophy of the neural plate and expansion of early neural genes (sox3 and otx2), but this is not the result of increased proliferation or expanded neural-inducing mesoderm. The neural plate appears to be maintained in an immature state because otx2 expression is expanded and expression of en2, Krox20, proneural genes (Xnrgn1, neuroD) and a neural differentiation gene (n-tubulin) is repressed in foxD5a-expressing cells. These results indicate that foxD5a maintains an undifferentiated neural ectoderm after neural induction. Expression of foxD5a constructs fused with the engrailed repressor domain or with the VP16 activation domain demonstrates that FoxD5a acts as a transcriptional repressor in axis formation and neural plate expansion. Deletion constructs indicate that this activity requires the C-terminal domain of the protein.

Amino Acid Sequence↗
PubMed2006

Repression of transcription by TSGA/Jmjd1a, a novel interaction partner of the ETS protein ER71.

Testis-specific gene A (TSGA) was originally identified in rat and shown to be expressed within the testes. Here, we have cloned the murine homolog [also known as jumonji domain-containing 1a (Jmjd1a)] and for the first time characterized the TSGA protein and its functions. Although murine TSGA is expressed in testes, its mRNA is also present in many other tissues, including heart, thymus, liver, and skin. Immunostaining revealed that TSGA is a nuclear protein, whose N-terminus contains a putative nuclear localization signal. TSGA displays significant homology to a suspected tumor suppressor and coactivator (5qNCA), to a thyroid hormone receptor interacting protein (TRIP8) and to the corepressor Hairless, pointing at a role of TSGA in transcription regulation. Indeed, TSGA contains several functional transcription repression domains. In addition, TSGA interacts both in vitro and in vivo with ER71 (ETS related 71), a transcription factor that is expressed in the testes of adult mice and during embryogenesis. Specifically, the N-terminus of TSGA and the C-terminus of ER71 are primarily engaged in their complex formation. Furthermore, TSGA impairs the ability of ER71 to activate transcription from the matrix metalloproteinase-1 promoter. Thus, TSGA may modulate the function of ER71 and thereby affect spermatogenesis as well as embryonic development.

Amino Acid Sequence↗
PubMed1999

A mechanism for Rb/p130-mediated transcription repression involving recruitment of the CtBP corepressor.

Previous work has demonstrated the critical role for transcription repression in quiescent cells through the action of E2F-Rb or E2F-p130 complexes. Recent studies have shown that at least one mechanism for this repression involves the recruitment of histone deacetylase. Nevertheless, these studies also suggest that other events likely contribute to E2F/Rb-mediated repression. Using a yeast two-hybrid screen to identify proteins that specifically interact with the Rb-related p130 protein, we demonstrate that p130, as well as Rb, interacts with a protein known as CtIP. This interaction depends on the p130 pocket domain, which is important for repression activity, as well as an LXCXE sequence within CtIP, a motif previously shown to mediate interactions of viral proteins with Rb. CtIP interacts with CtBP, a protein named for its ability to interact with the C-terminal sequences of adenovirus E1A. Recent work has demonstrated that the Drosophila homologue of CtBP is a transcriptional corepressor for Hairy, Knirps, and Snail. We now show that both CtIP and CtBP can efficiently repress transcription when recruited to a promoter by the Gal4 DNA binding domain, thereby identifying them as corepressor proteins. Moreover, the full repression activity of CtIP requires a PLDLS domain that is also necessary for the interaction with CtBP. We propose that E2F-mediated repression involves at least two events, either the recruitment of a histone deacetylase or the recruitment of the CtIP/CtBP corepressor complex.

Alcohol Oxidoreductases↗
PubMed2002

The MYST domain acetyltransferase Chameau functions in epigenetic mechanisms of transcriptional repression.

Reversible acetylation of histone tails plays an important role in chromatin remodelling and regulation of gene activity. While modification by histone acetyltransferase (HAT) is usually linked to transcriptional activation, we provide here evidence for HAT function in several types of epigenetic repression. Chameau (Chm), a new Drosophila member of the MYST HAT family, dominantly suppresses position effect variegation (PEV), is required for the maintenance of Hox gene silencing by Polycomb group (PcG) proteins, and can partially substitute for the MYST Sas2 HAT in yeast telomeric position effect (TPE). Finally, we provide in vivo evidence that the acetyltransferase activity of Chm is required in these processes, since a variant protein mutated in the catalytic domain no longer rescues PEV modification, telomeric silencing of SAS2-deficient yeast cells, nor lethality of chm mutant flies. These findings emphasize the role of an acetyltransferase in gene silencing, which supports, according to the histone code hypothesis, that transcription at a particular locus is determined by a precise combination of histone tail modifications rather than by overall acetylation levels.

Acetyltransferases↗
PubMed2005

cis-regulatory logic of short-range transcriptional repression in Drosophila melanogaster.

Bioinformatics analysis of transcriptional control is guided by knowledge of the characteristics of cis-regulatory regions or enhancers. Features such as clustering of binding sites and co-occurrence of binding sites have aided enhancer identification, but quantitative predictions of enhancer function are not yet generally feasible. To facilitate the analysis of regulatory sequences in Drosophila melanogaster, we identified quantitative parameters that affect the activity of short-range transcriptional repressors, proteins that play key roles in development. In addition to the previously noted distance dependence, repression is strongly influenced by the stoichiometry, affinity, spacing, and arrangement of activator binding sites. Repression is insensitive to the type of activation domain, suggesting that short-range repression may primarily affect activators at the level of DNA binding. The activity of several short-range, but not long-range, repressors is circumscribed by the same quantitative parameters. This cis-regulatory "grammar" may aid the identification of enhancers regulated by short-range repressors and facilitate bioinformatic prediction of the functional output of transcriptional regulatory sequences.

Animals↗
PubMed2005

Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1.

Amphotericin B (AmB) is widely used for treating severe systemic fungal infections. However, long-term AmB treatment is invariably associated with adverse effects such as anemia. The erythropoietin (EPO) suppression by AmB has been proposed to contribute to the development of anemia. However, the mechanism whereby EPO is suppressed remains obscure. In this study, we investigated the possibility that AmB inhibits the transcription of the EPO gene by inactivating HIF-1, which is a known key transcription factor and regulator of EPO expression. EPO mRNA levels were markedly attenuated by AmB treatment both in rat kidneys and in Hep3B cells. AmB inactivated the transcriptional activity of HIF-1alpha, but did not affect the expression or localization of HIF-1 subunits. Moreover, AmB was found to specifically repress the C-terminal transactivation domain (CAD) of HIF-1alpha, and this repression by AmB required Asn803, a target site of the factor-inhibiting HIF-1 (FIH); moreover, this repressive effect was reversed by FIH inhibitors. Furthermore, AmB stimulated CAD-FIH interaction and inhibited the p300 recruitment by CAD. We propose that this mechanism underlies the unexplained anemia associated with AmB therapy.

Amphotericin B↗
PubMed1995

Direct transcriptional repression by pRB and its reversal by specific cyclins.

It was recently shown that the E2F-pRB complex is a negative transcriptional regulator. However, it was not determined whether the whole complex or pRB alone is required for repression. Here we show that pRB and the related protein p107 are capable of direct transcriptional repression independent of E2F. When fused to the DNA binding domain of GAL4, pRB or p107 represses transcription of promoters with GAL4 binding sites. Thus, E2F acts as a tether for pRB or p107 but is not actively involved in repression of other enhancers. This function of pRB maps to the pocket and is abrogated by mutation of this domain. This result suggests an intriguing model in which the pocket has a dual function, first to bind E2F and second to repress transcription directly, possibly through interaction with other proteins. We also show that direct transcriptional repression by pRB is regulated by phosphorylation. Mutations which render pRB constitutively hypophosphorylated potentiate repression, while phosphorylation induced by cyclin A or E reduces repression ninefold.

Base Sequence↗
PubMed2005

Multiple pathways tether telomeres and silent chromatin at the nuclear periphery: functional implications for sir-mediated repression.

The positioning of chromosomal domains within interphase nuclei is thought to contribute to establishment and maintenance of epigenetic control. Using GFP-tagged chromosomal domains, LexA-fusion targeting and live microscopy, we investigated mechanisms through which chromatin can be anchored to the nuclear envelope (NE). We find that a subdomain of the silencing information regulator Sir4 (Sir4(PAD)) and yKu80 are sufficient to tether a chromatin region to the nuclear periphery, independently of their silencing function. Sir4(PAD) interacts with Esc1 (Establishes Silent Chromatin 1), a large acidic protein, localized at the nuclear periphery in the absence of Sir4 and yKu. Sir4 also binds to the periphery through yKu80, whose perinuclear ligand is unidentified. Both pathways are involved in the localization of natural telomeres. To show that silent chromatin can also mediate anchorage, we uncoupled the HMR silent mating-type locus from the chromosome using inducible site-specific recombination. Real-time cytological techniques reveal the position and dynamics of the excised locus. We show that the silent HMR ring associates with the NE in a SIR-dependent manner, while derepressed excised rings move without detectable constraint throughout the nucleoplasm. Dual anchoring pathways thus cooperate to generate high concentrations of SIR proteins in perinuclear foci, which in turn promote repression.

Cell Nucleus↗
PubMed1997

Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein.

Hepatitis C virus (HCV) is the major cause of non-A non-B hepatitis and a leading cause of liver dysfunction worldwide. While the current therapy for chronic HCV infection is parenteral administration of type 1 interferon (IFN), only a fraction of HCV-infected individuals completely respond to treatment. Previous studies have correlated the IFN sensitivity of strain HCV-1b with mutations within a discrete region of the viral nonstructural 5A protein (NS5A), termed the interferon sensitivity determining region (ISDR), suggesting that NS5A may contribute to the IFN-resistant phenotype of HCV. To determine the importance of HCV NS5A and the NS5A ISDR in mediating HCV IFN resistance, we tested whether the NS5A protein could regulate the IFN-induced protein kinase, PKR, a mediator of IFN-induced antiviral resistance and a target of viral and cellular inhibitors. Using multiple approaches, including biochemical, transfection, and yeast genetics analyses, we can now report that NS5A represses PKR through a direct interaction with the protein kinase catalytic domain and that both PKR repression and interaction requires the ISDR. Thus, inactivation of PKR may be one mechanism by which HCV avoids the antiviral effects of IFN. Finally the inhibition of the PKR protein kinase, by NS5A is the first described function for this HCV protein.

Antiviral Agents↗
PubMed2006

General mutagenesis of F plasmid TraI reveals its role in conjugative regulation.

Bacteria commonly exchange genetic information by the horizontal transfer of conjugative plasmids. In gram-negative conjugation, a relaxase enzyme is absolutely required to prepare plasmid DNA for transit into the recipient via a type IV secretion system. Here we report a mutagenesis of the F plasmid relaxase gene traI using in-frame, 31-codon insertions. Phenotypic analysis of our mutant library revealed that several mutant proteins are functional in conjugation, highlighting regions of TraI that can tolerate insertions of a moderate size. We also demonstrate that wild-type TraI, when overexpressed, plays a dominant-negative regulatory role in conjugation, repressing plasmid transfer frequencies approximately 100-fold. Mutant TraI proteins with insertions in a region of approximately 400 residues between the consensus relaxase and helicase sequences did not cause conjugative repression. These unrestrictive TraI variants have normal relaxase activity in vivo, and several have wild-type conjugative functions when expressed at normal levels. We postulate that TraI negatively regulates conjugation by interacting with and sequestering some component of the conjugative apparatus. Our data indicate that the domain responsible for conjugative repression resides in the central region of TraI between the protein's catalytic domains.

Conjugation, Genetic↗
PubMed1999

Position effect variegation at the mating-type locus of fission yeast: a cis-acting element inhibits covariegated expression of genes in the silent and expressed domains.

Schizosaccharomyces pombe switches its mating type by transposing a copy of unexpressed genes from the respective mat2 or mat3 cassettes to mat1. The donor cassettes are located in a silent domain that is separated from the expressed mat1 cassette by the L region. We monitored the expression of ade6 from sites in the L region and examined the relationship between the expression state at these sites and at sites within the silent domain. Results indicate that: (1) the silent domain extends into the L region, but repression is gradually alleviated with increasing distance from mat2, and overexpression of swi6 enhances PEV in the L region; (2) a transcriptionally active chromatin state, associated with reporter gene expression in the L region, spreads toward the silent domain; (3) a cis-acting element, located at the junction between the L region and mat2-P, ensures repression in the silent domain, regardless of the expression state in the L region; and (4) repression in mat1-P cells is less stringently controlled than in mat1-M cells. We discuss the functional organization of the mat region and genetic elements that ensure separation between repressed and derepressed domains.

Adenine↗
PubMed2004

Transcriptional activity of serum amyloid A-activating factor-1 is regulated by distinct functional modules.

Serum amyloid A-activating transcription factor-1 (SAF-1) plays a major role in regulating transcription of several inflammation-responsive genes, including SAA and matrix metalloproteinase-1, that are implicated in the pathogenesis of reactive secondary amyloidosis, atherosclerosis, and arthritis. SAF-1 is a 477-amino acid protein with six zinc fingers. Its activation during inflammatory condition by a phosphorylation event that leads to an altered structure suggested possible structural modification of this protein as a leading cause of higher activity. However, no information is available regarding structural features that might regulate its activity. Here, we have characterized its functional domains, delineating activation and repression modules, DNA binding, and nuclear localization activities. Using GAL4AD chimeras and a DNA-binding assay with proteins prepared from various deletion constructs, the core DNA-binding domain of SAF-1 is mapped between amino acids 282 and 361, which contain second, third, and fourth zinc fingers. Results from several deletion and point mutants using green fluorescent protein reporter show that SAF-1 contains two independent nuclear localization signals; one is composed of a stretch of basic amino acids, and the other is a bipartite signal located within the core DNA-binding domain. SAF-1 contains several negative and positively functioning transactivation modules clustered at the two ends of this protein. Removal of any one of the terminal negative modules renders the SAF-1 protein functionally very active. These findings suggest that the terminal repression modules act in conjunction to regulate the functional activity of this protein.

Amino Acid Sequence↗
PubMed2003

A composite motif of the Drosophila morphogenetic protein bicoid critical to transcription control.

Bicoid is a molecular morphogen-controlling embryonic patterning in Drosophila. It is a homeodomain-containing protein that activates specific target genes during early embryogenesis. Our recent studies have identified a domain of Bcd located outside its homeodomain and referred to as a self-inhibitory domain that can dramatically repress its own ability to activate transcription. Here we present evidence that the self-inhibitory function is evolutionarily conserved. A systematic analysis of this domain reveals a composite 10-amino acid motif with interdigitating residues that regulate Bcd activity in opposite manners. Mutations within the Bcd motif can exert their respective effects when the self-inhibitory domain is grafted to an entirely heterologous activator, but they do not affect DNA binding in vitro or subcellular localization of Bcd in cells. We further show that the self-inhibitory domain of Bcd can interact with Sin3A, a component of the histone deacetylase co-repressor complex. Our study suggests that the activity of Bcd is intricately controlled by multiple mechanisms involving the actions of co-repressor proteins.

Amino Acid Sequence↗
PubMed2003

Global regulation of Hox gene expression in C. elegans by a SAM domain protein.

Polycomb group (PcG)-mediated repression of C. elegans Hox genes has not been demonstrated, and genes homologous to components of one of the PcG complexes (PRC1) have not been identified in the C. elegans genome. We find that a mechanism of general Hox gene repression exists in C. elegans, carried out in part by SOP-2, a protein related to, but not orthologous with, any PcG protein. sop-2 mutations lead to widespread ectopic expression of Hox genes and homeotic transformations. SOP-2 contains a SAM domain, a self-associating protein domain found in other repressors, including a core component of PRC1 and ETS transcription factors. Phylogenetic analysis indicates that this domain is more closely related to those of the ETS family than to those of PcG proteins. The results suggest that global repression of Hox genes has been taken over by a different branch of the SAM domain family during the evolution of nematodes.

Amino Acid Sequence↗