A5052188105- RNA and protein synthesis mechanisms
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Radiopharmaceutical Chemistry and Applications
- DNA Repair Mechanisms
- Mechanisms of cancer metastasis
- DNA and Nucleic Acid Chemistry
- Medical Imaging Techniques and Applications
- Bacterial Genetics and Biotechnology
- Hydrogen Storage and Materials
- RNA modifications and cancer
- Advanced biosensing and bioanalysis techniques
- Genomics, phytochemicals, and oxidative stress
- Parathyroid Disorders and Treatments
- Selenium in Biological Systems
- RNA Interference and Gene Delivery
- Metalloenzymes and iron-sulfur proteins
- Genetic Syndromes and Imprinting
- Bacteriophages and microbial interactions
- CRISPR and Genetic Engineering
- Lanthanide and Transition Metal Complexes
- Molecular Biology Techniques and Applications
- HER2/EGFR in Cancer Research
- Glutathione Transferases and Polymorphisms
- Infections and bacterial resistance
Institute of Structural and Molecular Biology
2020-2024
Birkbeck, University of London
2020-2024
University College London
2023-2024
Institute of Cancer Research
2015-2022
Institut Pasteur
2009-2015
Centre National de la Recherche Scientifique
2012-2013
Délégation Paris 7
2012
Sorbonne Paris Cité
2012
Université Paris Cité
2012
TFIIB-related factor 2 (Brf2) is a member of the family TFIIB-like core transcription factors. Brf2 recruits RNA polymerase (Pol) III to type gene-external promoters, including U6 spliceosomal and selenocysteine tRNA genes. Found only in vertebrates, has been linked tumorigenesis but underlying mechanisms remain elusive. We have solved crystal structures human Brf2-TBP complex bound natural obtaining detailed view molecular interactions occurring at Brf2-dependent Pol promoters highlighting...
In eukaryotes, RNA Polymerase (Pol) III is specialized for the transcription of tRNAs and other short, untranslated RNAs. Pol a determinant cellular growth lifespan across eukaryotes. Upregulation observed in cancer causative mutations have been described neurodevelopmental disorders hypersensitivity to viral infection. Here, we report cryo-EM reconstruction at 4.0 Å human III, allowing mapping rationalization reported genetic mutations. Mutations causing defects cluster hotspots affecting...
Abstract Initiation of gene transcription by RNA polymerase (Pol) III requires the activity TFIIIB, a complex formed Brf1 (or Brf2), TBP (TATA-binding protein), and Bdp1. TFIIIB is required for recruitment Pol to promote transition from closed an open pre-initiation complex, process dependent on Bdp1 subunit. Here, we present crystal structure Brf2–TBP–Bdp1 bound DNA at 2.7 Å resolution, integrated with single-molecule FRET analysis in vitro biochemical assays. Our study provides structural...
Abstract The TATA-binding protein (TBP) and a transcription factor (TF) IIB-like are important constituents of all eukaryotic initiation complexes. reason for the emergence strict requirement additional Bdp1 in RNA polymerase (RNAP) III system, however, remained elusive. A poorly studied aspect this context is effect DNA strain arising from compaction transcriptional activity on complex formation. We made use origami-based force clamp to follow assembly human complexes RNAP II systems at...
The metastasis suppressor protein NME1 is an evolutionarily conserved and multifunctional enzyme that plays important role in suppressing the invasion of tumour cells. nucleoside diphosphate kinase (NDPK) activity well recognized balancing intracellular pools nucleotide diphosphates triphosphates to regulate cytoskeletal rearrangement cell motility, endocytosis, trafficking, metastasis. In addition, was found function as a protein-histidine kinase, 3′-5′ exonuclease geranyl/farnesyl...
Abstract RNA polymerase II (Pol II) carries out transcription of both protein-coding and non-coding genes. Whereas Pol initiation at genes has been studied in detail, genes, such as small nuclear (snRNA) is less well understood the structural level. Here, we study snRNA gene promoters show that snRNA-activating protein complex (SNAPc) enables DNA opening independent TFIIE TFIIH vitro. We then resolve cryo-EM structures SNAPc-containing IIpre-initiation (PIC) assembled on U1 U5 promoters. The...
RNA polymerase II (Pol II) small nuclear (snRNA) promoters and type 3 Pol III have highly similar structures; both contain an interchangeable enhancer “proximal sequence element” (PSE), which recruits the SNAP complex (SNAPc). The main distinguishing feature is presence, in only, of a TATA box, determines specificity. To understand mechanism by absence or presence box results specific recruitment, we examined how SNAPc general transcription factors required for SNAPc-dependent genes (i.e.,...
Terminal deoxynucleotidyltransferase (Tdt) and DNA polymerase μ (pol μ) are two eukaryotic highly similar proteins involved in processing repair. Despite their high sequence identity, they differ widely activity: pol has a templated activity, whereas Tdt non-templated one. Loop1, first described when the structure was solved, been invoked as major structural determinant of this difference. Here we describe attempts to transform into with minimal number mutations around Loop1. First effect on...
Terminal deoxynucletidyl transferase (TdT) is overexpressed in some cancer types, where it might compete with pol μ during the mutagenic repair of double strand breaks (DSBs) through nonhomologous end joining (NHEJ) pathway. Here we report discovery and characterization pyrrolyl indolyl diketo acids that specifically target TdT behave as nucleotide-competitive inhibitors. These compounds show a selective toxicity toward MOLT-4 compared to HeLa cells correlate well vitro selectivity for TdT....
Coenzyme A (CoA) is a key cellular metabolite which participates in diverse metabolic pathways, regulation of gene expression and the antioxidant defense mechanism. Human NME1 (hNME1), moonlighting protein, was identified as major CoA-binding protein. Biochemical studies showed that hNME1 regulated by CoA through both covalent non-covalent binding, leads to decrease nucleoside diphosphate kinase (NDPK) activity. In this study, we expanded knowledge on previous findings focusing mode binding...
Abstract The TATA-binding protein (TBP) and a transcription factor (TF) IIB-like compound the fundamental core of all eukaryotic initiation complexes. reason for emergence strict requirement additional intiation Bdp1, which is unique to RNA polymerase (RNAP) III sytem, however, remained elusive. A poorly studied aspect in this context effect DNA strain, that arises from compaction transcriptional activity, on efficiency complex formation. We made use new nanotechnological tool –...
Introduction Small subsets of RNA Polymerase (Pol) III genes, including the selenocysteine tRNA gene, rely on presence BRF2 transcription factor. Previously, we identified a redox-sensitive switch (Cysteine 361) which, when oxidised, can downregulate Pol at all BRF2-dependent promoters (Gouge et al. 2015). In cancer cells, is frequently amplified and/or overexpressed. We hypothesised that activation required for maintaining high levels tRNA, as well selenoproteins, during prolonged oxidative...