A5045443541- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Fungal and yeast genetics research
- RNA modifications and cancer
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Plant Molecular Biology Research
- Receptor Mechanisms and Signaling
- RNA and protein synthesis mechanisms
- Sirtuins and Resveratrol in Medicine
- CRISPR and Genetic Engineering
- Plant Virus Research Studies
- Hormonal Regulation and Hypertension
- Apelin-related biomedical research
- PARP inhibition in cancer therapy
- DNA Repair Mechanisms
- Peptidase Inhibition and Analysis
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Parkinson's Disease Mechanisms and Treatments
- Calcium signaling and nucleotide metabolism
- Epigenetics and DNA Methylation
- Neurotransmitter Receptor Influence on Behavior
- Protein Kinase Regulation and GTPase Signaling
- Neuroscience and Neuropharmacology Research
- Endoplasmic Reticulum Stress and Disease
McGill University
2015-2024
Rockefeller University
2006-2007
Harvard University
1999-2006
University of Toronto
1998-2005
Transcriptional silencing at the budding yeast silent mating type (HM) loci and telomeric DNA regions requires Sir2, a conserved NAD-dependent histone deacetylase, Sir3, Sir4, histones H3 H4, several DNA-binding proteins. Silencing ribosomal (rDNA) repeats complex containing Net1, Cdc14. Here we show that native Sir2/Sir4 is composed solely of Sir2 Sir4 Sir3 not associated with other We further initial binding to sites nucleate silencing, accompanied by partial Sir2-dependent deacetylation,...
Histone acetylation affects many nuclear processes including transcription, chromatin assembly, and DNA damage repair. Acetylation of histone H3 lysine 56 (H3 K56ac) in budding yeast occurs during mitotic S phase persists Here, we show that K56ac is also present premeiotic conserved fission yeast. Furthermore, the modification not observed absence chaperone Asf1. asf1delta K56R mutants exhibit similar sensitivity to damaging agents. Mutational analysis Asf1 demonstrates correlates with (i)...
The Saccharomyces cerevisiae silencing protein Sir2 is the founding member of a universally conserved family proteins that have been shown to possess NAD-dependent histone deacetylation and ADP-ribosylation activities. Here we show by coupled cleavage high-energy bond links ADP-ribose moiety NAD nicotinamide. Analysis products revealed presence nicotinamide, ADP-ribose, third product appeared be related ADP-ribose. With use label transfer experiments, acetyl group in substrate transferred...
Transcription by RNA polymerase II (polII) is accompanied dramatic changes in chromatin structure. Numerous enzymatic activities contribute to these changes, including ATP-dependent nucleosome remodeling enzymes and histone modifying enzymes. Recent studies budding yeast document a modification pathway associated with polII transcription, whereby ubiquitylation of H2B leads methylation H3 on specific lysine residues. Although this series events appears be highly conserved among eukaryotes,...
Transcript elongation by RNA polymerase II (RNAPII) is accompanied conserved patterns of histone modification. Whereas modifications have established roles in transcription initiation, their functions during are not understood. Mono-ubiquitylation H2B (H2Bub1) plays a key role coordinating co-transcriptional modification promoting site-specific methylation H3. H2Bub1 also regulates gene expression through an unidentified, methylation-independent mechanism. Here we reveal bidirectional...
Nucleosome composition actively contributes to chromatin structure and accessibility. Cells have developed mechanisms remove or recycle histones, generating a landscape of differentially aged nucleosomes. This study aimed create high-resolution, genome-wide map nucleosome turnover in Schizosaccharomyces pombe. The recombination-induced tag exchange (RITE) method was used replication-independent through the appearance new histone H3 disappearance preservation old H3. location histones...
The divergently transcribed DIT1 and DIT2 genes of Saccharomyces cerevisiae, which belong to the mid-late class sporulation-specific genes, are subject Ssn6-Tup1-mediated repression in mitotic cells. Ssn6-Tup1 complex, is required for diverse sets coordinately regulated known be recruited target by promoter-specific DNA-binding proteins. In this study, we show that a 42-bp negative regulatory element (NRE) present DIT1-DIT2 intergenic region consists two distinct subsites multimer each...
Gene silencing in the budding yeast Saccharomyces cerevisiae requires enzymatic activity of Sir2 protein, a highly conserved NAD-dependent deacetylase. In order to study native Sir2, we purified and characterized two complexes: Sir2/Sir4 complex, which mediates at mating-type loci telomeres, RENT ribosomal DNA repeats. Analyses protein compositions these complexes confirmed previously described interactions. We show that assembly into does not alter its selectivity for acetylated substrates,...
Cyclin-dependent kinase 9 (Cdk9) promotes elongation by RNA polymerase II (RNAPII), mRNA processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved RNAPII factor Spt5 itself, but how these different modifications mediate functions is not known. Here we describe two Cdk9-dependent pathways in fission yeast Schizosaccharomyces pombe that involve distinct targets elicit biological outcomes. Phosphorylation of creates a direct binding...
A comprehensive understanding of signalling downstream GPCRs requires a broad approach to capture novel modalities in addition established pathways. Here, using an array sixteen validated BRET-based biosensors, we analyzed the ability seven different β-adrenergic ligands engage five distinct pathways β1-adrenergic receptor (β1AR). In generating signatures and capturing functional selectivity for toward these pathways, also revealed coupling that have not previously been ascribed βAR. These...
Gene silencing involves the assembly of DNA into specialized chromatin domains that are inaccessible to trans-acting factors and epigenetically inherited. In budding yeast Saccharomyces cerevisiae, silent heterochromatic occur at telomeres, mating type loci, rDNA repeats. At telomeres requires Sir2, Sir3 Sir4 proteins, conserved N-termini histones H3 H4, a number factors. The Sir proteins form multimeric complex binds preferentially deacetylated nucleosomes through subunits. Sir2 subunit...
Mono-ubiquitylation of histone H2B (H2Bub1) and phosphorylation elongation factor Spt5 by cyclin-dependent kinase 9 (Cdk9) occur during transcription RNA polymerase II (RNAPII), are mutually dependent in fission yeast. It remained unclear whether Cdk9 H2Bub1 cooperate to regulate the expression individual genes. Here, we show that inhibition or loss induces intragenic antisense ∼10% yeast genes, with each perturbation affecting largely distinct subsets; ablation both pathways de-represses...
Abstract As with many G protein-coupled receptors (GPCRs), the signalling pathways regulated by dopamine D1 receptor (D1R) are dynamic, cell type-specific, and can change in face of disease or drug exposures. In striatal neurons, D1R activates cAMP/protein kinase A (PKA) signalling. However, Parkinson’s (PD), alterations this pathway lead to functional upregulation extracellular kinases 1/2 (ERK1/2), contributing l -DOPA-induced dyskinesia (LID). order detect activation vivo study...
Transcription by RNA polymerase II (RNAPII) is accompanied a conserved pattern of histone modifications that plays important roles in regulating gene expression. The establishment this requires phosphorylation both Rpb1 (the largest RNAPII subunit) and the elongation factor Spt5 on their respective C-terminal domains (CTDs). Here we interrogated individual CTD phospho-sites directing co-transcriptional fission yeast Schizosaccharomyces pombe. Steady-state levels methylation at H3 lysines 4...
Pathological cardiac hypertrophy is driven by neurohormonal activation of specific G protein-coupled receptors (GPCRs) in cardiomyocytes and accompanied large-scale changes cardiomyocyte gene expression. These transcriptional require activity positive transcription elongation factor b (P-TEFb), which recruited to target genes the bromodomain protein Brd4 or super complex (SEC). Here, we describe GPCR-specific regulation these P-TEFb complexes a novel mechanism for activating primary neonatal...