Alcide Barberis

Vir Biotechnology (Switzerland)

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Transcription Activation in Eukaryotic Cells

Encyclopedia of Life Sciences (2003)

Alcide Barberis Michael Petrascheck

Abstract Transcription activation is the first step in eukaryotic gene expression. Gene regulation, which is about turning on and off expression of specific protein‐coding genes in response to environmental changes, during development and in differentiated cells, widely occurs at the level of transcription activation. This is mostly achieved by DNA‐binding proteins that can control the specificity of the RNA polymerase II enzyme.

Transcription

RNA polymerase II

Eukaryotic transcription

General transcription factor

Response element

10.1038/npg.els.0003303

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Citations (17)

In Silico Discovery of β-Secretase Inhibitors

Journal of the American Chemical Society (2006)

Danzhi Huang Urs Lüthi Peter Kolb Marco Cecchini Alcide Barberis

Alzheimer's disease, the most common amyloid-associated disorder, accounts for the majority of the dementia diagnosed after the age of 60. The cleavage of the β-amyloid precursor protein is initiated by β-secretase (BACE-1), a membrane-bound aspartic protease, which has emerged as an important but difficult protein target. Here, an in silico screening approach consisting of fragment-based docking, ligand conformational search by a genetic algorithm, and evaluation of free energy of binding was used to identify low-molecular-weight inhibitors of BACE-1. More than 300 000 small molecules were docked and about 15 000 prioritized according to a linear interaction energy model with evaluation of solvation by continuum electrostatics. Eighty-eight compounds were tested in vitro, and 10 of them showed an IC50 value lower than 100 μM in a BACE-1 enzymatic assay. Interestingly, the 10 active compounds shared a triazine scaffold. Moreover, four of them were active in an assay with mammalian cells (EC50 < 20 μM), indicating that they are cell-permeable. Therefore, these triazine derivatives are very promising lead candidates for BACE-1 inhibition. The discoveries of this series and two other series of nonpeptidic BACE-1 inhibitors demonstrate the usefulness of our in silico high-throughput screening approach.

Docking (animal)

Triazine

Lead compound

Implicit solvation

Molecular model

10.1021/ja0573108

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Citations (83)

Yeast growth selection system for the identification of cell-active inhibitors of β-secretase

Biochimica et Biophysica Acta (BBA) - General Subjects (2004)

Oliver Middendorp Christopher Ortler Ulf Neumann Paolo Paganetti Urs Lüthi

10.1016/j.bbagen.2004.05.004

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Citations (27)

Review

Biological Chemistry (1998)

Alcide Barberis Luc Gaudreau

In yeast cells, interaction between a DNA-bound protein and a single component of the RNA polymerase II (poIII) holoenzyme is sufficient to recruit the latter to a promoter and thereby activate gene transcription. Here we review results which have suggested such a simple mechanism for how genes can be turned on. The series of experiments which eventually led to this model was originally instigated by studying gene expression in a yeast strain which carries a point mutation in Gal11, a component of the poIII holoenzyme. In cells containing this mutant protein termed Gall11P, a derivative of the transcriptional activator Gal4 devoid of any classical activating region is turned into a strong activator. This activating function acquired by an otherwise silent DNA-binding protein is solely due to a novel and fortuitous interaction between Gal11P and a fragment of the Gal4 dimerization region generated by the P mutation. The simplest explanation for these results is that tethering Gal11 to DNA recruits the poIII holoenzyme and, consequently, activates gene transcription. Transcription factors that are believed not to be integral part of the poIII holoenzyme but are nevertheless required for this instance of gene activation, e.g. the TATA-binding TFIID complex, may bind DNA cooperatively with the holoenzyme when recruited to a promoter, thus forming a complete poIII preinitiation complex. One prediction of this model is that recruitment of the entire poIII transcription complex and consequent gene activation can be achieved by tethering different components to DNA. Indeed, fusion of a DNA-binding domain to a variety of poIII holoenzyme components and TFIID subunits leads to activation of genes bearing the recognition site for the DNA-binding protein. These results imply that accessory factors, which are required to remove or modify nucleosomes do not need to be directly contacted by activators, but can rather be engaged in the activation process when the poIII complex is recruited to DNA. In fact, recruitment of the poIII holoenzyme suffices to remodel nucleosomes at the PHO5 promoter and presumably at many other promoters. Other events in the process of gene expression following recruitment of the transcription complex, e.g. initiation, promoter clearance, elongation and termination, could unravel as a consequence of the recruitment step and the formation of an active preinitiation complex on DNA. This view does not exclude the possibility that classical activators also act directly on chromatin remodeling and post-recruitment steps to regulate gene expression.

Transcription preinitiation complex

General transcription factor

Transcription

Bacterial transcription

RNA polymerase II

10.1515/bchm.1998.379.12.1397

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Citations (18)

Yeast as a screening tool

Drug Discovery Today Technologies (2005)

Alcide Barberis Tea Gunde Catherine Berset Stephan Audetat Urs Lüthi

10.1016/j.ddtec.2005.05.022

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Citations (51)

Novel Yeast Cell-Based Assay To Screen for Inhibitors of Human Cytomegalovirus Protease in a High-Throughput Format

Antimicrobial Agents and Chemotherapy (2006)

Valérie Cottier Alcide Barberis Urs Lüthi

The protease encoded by the human cytomegalovirus (HCMV) is an attractive target for antiviral drug development because of its essential function in viral replication. We describe here a cellular assay in the yeast Saccharomyces cerevisiae for the identification of small molecule inhibitors of HCMV protease by conditional growth in selective medium. In this system, the protease cleavage sequence is inserted into the N-(5'-phosphoribosyl)anthranilate isomerase (Trp1p), a yeast protein essential for cell proliferation in the absence of tryptophan. Coexpression of HCMV protease with the engineered Trp1p substrate in yeast cells results in site-specific cleavage and functional inactivation of the Trp1p enzyme, thereby leading to an arrest of cell proliferation. This growth arrest can be suppressed by the addition of validated HCMV protease inhibitors. The growth selection system presented here provides the basis for a high-throughput screen to identify HCMV protease inhibitors that are active in eukaryotic cells.

Cleavage (geology)

High-Throughput Screening

10.1128/aac.50.2.565-571.2006

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Citations (20)

MY010 anti-allergen antibodies for the treatment of multiple tree pollen allergies

Journal of Allergy and Clinical Immunology (2025)

Chiara Arena Dimitri Bieli Sandra Götschi Rahel Scheibling Yvonne Stark

10.1016/j.jaci.2024.12.508

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Synthesis of sperm and late histone cDNAs of the sea urchin with a primer complementary to the conserved 3' terminal palindrome: evidence for tissue-specific and more general histone gene variants.

Proceedings of the National Academy of Sciences (1985)

Meinrad Busslinger Alcide Barberis

We have cloned histone cDNAs from total RNA isolated from testis and from gastrula-stage embryos of the sea urchin Psammechinus miliaris. The reverse transcription of histone mRNAs was specifically primed with an oligonucleotide that is complementary to the conserved palindromic sequence present at the 3' end of nonpolyadenylated histone mRNAs. Two sperm H2B, two late H2B, and three late H2A variant cDNA clones were isolated and characterized by DNA sequence analysis. These cDNA clones were used to study the accumulation of histone mRNA during sea urchin embryogenesis. The different late H2A and H2B mRNAs are present in as few as 200 copies in the egg and each accumulate to 3-5 X 10(5) molecules in the gastrula embryo. One of the late mRNAs, the H2A-3 mRNA, is also abundant in testis RNA and codes for the H2A variant present in sperm chromatin. The late H2A-3 protein is therefore a more prevalent H2A variant of the sea urchin. In contrast, the two sperm H2B mRNAs are found in testes but not ovaries and embryos of the sea urchin, suggesting that the sperm H2B genes are expressed only during spermatogenesis. In addition, evidence for gene conversion between two late H2A gene variants is presented.

10.1073/pnas.82.17.5676

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Citations (58)

Coupling homologous recombination with growth selection in yeast: a tool for construction of random DNA sequence libraries

BioTechniques (2004)

Claudia Schaerer-Brodbeck Alcide Barberis

Sequence (biology)

10.2144/04372bm05

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Citations (11)

An adenovirus vector with a chimeric fiber incorporating stabilized single chain antibody achieves targeted gene delivery

Gene Therapy (2005)

Susan J. Hedley Adrian Auf der Maur S Hohn Dominik Escher Alcide Barberis

HEK 293 cells

10.1038/sj.gt.3302603

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Citations (66)