A5031780379- interferon and immune responses
- Cytokine Signaling Pathways and Interactions
- Cancer-related molecular mechanisms research
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- PI3K/AKT/mTOR signaling in cancer
- Cancer-related gene regulation
- RNA Research and Splicing
- Alzheimer's disease research and treatments
- Tryptophan and brain disorders
- RNA regulation and disease
- Cellular transport and secretion
- Quinazolinone synthesis and applications
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Genomics and Phylogenetic Studies
- Eosinophilic Disorders and Syndromes
- Metabolism and Genetic Disorders
- MicroRNA in disease regulation
- Biotin and Related Studies
- Viral-associated cancers and disorders
- Mitochondrial Function and Pathology
- Peptidase Inhibition and Analysis
- HVDC Systems and Fault Protection
- Neuroscience and Neuropharmacology Research
- Signaling Pathways in Disease
Mission Therapeutics (United Kingdom)
2022-2024
MRC Laboratory of Molecular Biology
2018-2021
MRC Mitochondrial Biology Unit
2013
Medical Research Council
2013
Abstract Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity cancer cells remains a priority. Using novel enzymatic inhibitor RNA methyltransferase METTL3, we demonstrate global decrease in N6-methyladenosine (m6A) results double-stranded (dsRNA) formation and profound cell-intrinsic interferon response. Through unbiased CRISPR screens, establish dsRNA-sensing signaling are...
Significance Mammalian complex I, the largest and most complicated enzyme of mitochondrial respiratory chain, is an L-shaped assembly 44 proteins with one arm in matrix orthogonal buried inner membrane. It put together from preassembled modules. This investigation concerns little studied process membrane module emanating both nuclear genomes. We have identified two protein factors C3orf1 TMEM126B, not found mature complex, that help this by putting subcomplexes. Defects I are increasingly...
Multiple proteins act co-operatively in mammalian clathrin-mediated endocytosis (CME) to generate endocytic vesicles from the plasma membrane. The principles controlling activation and organization of actin cytoskeleton during CME are, however, not fully understood. Here, we show that protein FCHSD2 is a major activator polymerization CME. deletion leads decreased ligand uptake caused by slowed pit maturation. recruited pits scaffold intersectin via an unusual SH3-SH3 interaction. its flat...
Abstract Post-transcriptional RNA modifications, the epitranscriptome, play important roles in modulating functions of species. Modifications rRNA are key for ribosome production and function. Identification characterization enzymes involved epitranscriptome shaping is instrumental elucidation functional specific modifications. Ten modified sites have been thus far identified mammalian mitochondrial rRNA. Enzymes responsible two these modifications not characterized. Here, we identify...
Abstract The field of epitranscriptomics continues to reveal how post-transcriptional modification RNA affects a wide variety biological phenomena. A pivotal challenge in this area is the identification modified residues within their sequence contexts. Mass spectrometry (MS) offers comprehensive solution by using analogous approaches shotgun proteomics. However, software support for analysis MS data inadequate at present and does not allow high-throughput processing. Existing solutions lack...
Abstract Many cellular processes, including ribosome biogenesis, are regulated through post-transcriptional RNA modifications. Here, a genome-wide analysis of the human mitochondrial transcriptome shows that 2’- O -methylation is limited to residues mitoribosomal large subunit (mtLSU) 16S mt-rRNA, introduced by MRM1, MRM2 and MRM3, with modifications installed latter two proteins being interdependent. controls respiration regulating mitoribosome biogenesis. In its absence, mtLSU particles...
The amount of any given protein in the brain is determined by rates its synthesis and destruction, which are regulated different cellular mechanisms. Here, we combine metabolic labeling live mice with global proteomic profiling to simultaneously quantify both flux proteins mouse models neurodegeneration. In multiple models, turnover increases were associated increasing pathology. This method distinguishes changes expression mediated from those degradation. AppNL-F knockin model Alzheimer's...
SINEUPs are a novel class of natural and synthetic non-coding antisense RNA molecules able to increase the translation target mRNA. They present modular organization comprising an unstructured target-specific domain, which sets specificity each individual SINEUP, structured effector is responsible for enhancement. In order design fully functional
<div>Abstract<p>Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity cancer cells remains a priority. Using novel enzymatic inhibitor RNA methyltransferase METTL3, we demonstrate global decrease in N6-methyladenosine (m6A) results double-stranded (dsRNA) formation and profound cell-intrinsic interferon response. Through unbiased CRISPR screens, establish...
Abstract METTL1 is an RNA methyltransferase that catalyzes N7-methylation on guanine at position 46 (m7G46) in a subset of transfer RNAs (tRNAs). These tRNAs are stabilized by m7G46, and this increases the translation mRNAs containing cognate codons. often over-expressed cancer tissue, its gene locus frequently amplified specific tumor types. Recent studies have shown reducing expression leads to growth inhibition highlighting enzyme as potential novel target for anti-cancer drugs. We...
<p>Gene expression changes + pathways</p>
<p>Proliferation + Apoptosis assays</p>
<p>METTL3 KD in B16 cell line</p>
<p>A20 lymphoma model data</p>
<p>Nanopore workflow</p>
<p>Nanopore workflow</p>
<p>METTL3 KD in B16 cell line</p>
<p>Co-culture assays + human PBMC data</p>
<p>Proliferation + Apoptosis assays</p>
<p>PDL1 expression + STM3006 pharmacokinetic studies</p>
<p>Co-culture assays + human PBMC data</p>