A5102772055- RNA modifications and cancer
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Genomics and Chromatin Dynamics
- RNA regulation and disease
- Retinal Development and Disorders
- Retinal and Macular Surgery
- interferon and immune responses
- CRISPR and Genetic Engineering
- Cellular transport and secretion
- Ocular Disorders and Treatments
- Physical Activity and Health
- DNA and Nucleic Acid Chemistry
- Molecular Biology Techniques and Applications
Human Technopole
2022-2025
Institute of Cancer Research
2017-2022
University of Manchester
2016
Wellcome Centre for Cell-Matrix Research
2016
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...
Introns of human transfer RNA precursors (pre-tRNAs) are excised by the tRNA splicing endonuclease TSEN in complex with kinase CLP1. Mutations TSEN/CLP1 occur patients pontocerebellar hypoplasia (PCH), however, their role disease is unclear. Here, we show that intron excision catalyzed tetrameric assembled from inactive heterodimers independently Splice site recognition involves mature domain and anticodon-intron base pair pre-tRNAs. The 2.1-Å resolution X-ray crystal structure a TSEN15-34...
RNA polymerase III (Pol III) transcribes short, essential RNAs, including the U6 small nuclear (snRNA). At snRNA genes, Pol is recruited by Activating Protein Complex (SNAPc) and a Brf2-containing TFIIIB complex, forming pre-initiation complex (PIC). Uniquely, SNAPc also recruits II at remaining splicesosomal genes (U1, 2, 4 5). The mechanism of cross-polymerase engagement role SNAPC2 SNAPC5 subunits remain poorly defined. Here, we present cryo-EM structures full-length SNAPc-containing PIC...
Retinoschisin, an octameric retinal-specific protein, is essential for retinal architecture with mutations causing X-linked retinoschisis (XLRS), a monogenic form of macular degeneration. Most XLRS-associated cause intracellular retention, however subset are secreted as octamers and the their pathology ill-defined. Therefore, here we investigated solution structure retinoschisin monomer impact two XLRS-causing mutants using combinatorial approach biophysics cryo-EM. The has elongated which...
Transcription of the ribosomal RNA precursor by polymerase (Pol) I is a major determinant cellular growth, and dysregulation observed in many cancer types. Here, we present purification human Pol from cells carrying genomic GFP fusion on largest subunit allowing structural functional analysis enzyme across species. In contrast to yeast, carries single-subunit stalk, vitro transcription indicates reduced proofreading activity. Determination cryo-EM reconstruction close-to-native state...
Abstract Introns of human transfer RNA precursors (pre-tRNAs) are excised by the tRNA splicing endonuclease TSEN in complex with kinase CLP1. Mutations TSEN/CLP1 occur patients pontocerebellar hypoplasia (PCH), however, their role disease is unclear. Here, we show that intron excision catalyzed tetrameric assembled from inactive heterodimers independently Splice site recognition involves mature domain and anticodon-intron base pair pre-tRNAs. The 2.1-Å resolution X-ray crystal structure a...
Abstract RNA polymerase III (Pol III) is specialized in the transcription of short, essential RNAs, including U6 small nuclear RNAs (snRNAs). At snRNA genes, Pol recruited by Activating Protein Complex (SNAPc) forming, together with a Brf2-containing TFIIIB complex, transcriptionally competent pre-initiation complex (PIC). Additionally, SNAPc responsible for recruitment II at remaining snRNAs genes (U1, 2, 4 and 5), representing unique example multi subunit factor shared among different...
Abstract Transcription of the ribosomal RNA precursor by polymerase (Pol) I is a major determinant cellular growth and dysregulation observed in many cancer types. Here, we present purification human Pol from cells carrying genomic GFP-fusion on largest subunit allowing structural functional analysis enzyme across species. In contrast to yeast, carries single-subunit stalk vitro transcription indicates reduced proofreading activity. Determination cryo-EM reconstruction close-to-native state...
ABSTRACT In eukaryotes, RNA Polymerase (Pol) III is the enzyme specialised for transcription of entire pool tRNAs and several other short, essential, untranslated RNAs. Pol a critical determinant cellular growth lifespan across eukaryotic kingdom. Upregulation often observed in cancer cells causative mutations have been described patients affected by severe neurodevelopmental disorders hypersensitivity to viral infection. Harnessing CRISPR-Cas9 genome editing HeLa cells, we isolated...