The Biology of RNA polymerase III.
RNA polymerase (pol) III transcribes genes to produce tRNA and an eclectic mix of other short non-coding RNAs. Our research focuses on the molecular mechanisms and functional consequences of pol III regulation during cell differentiation, growth, proliferation and oncogenic transformation. This involves analyses of transcription factors and chromatin. We are also engaged in a programme of synthetic bioengineering aimed at enhancing production of recombinant products by manipulating pol III activity.
Recombinant monoclonal antibodies are a powerful class of therapeutics that are used to treat a wide range of diseases, including cancers and inflammatory disorders. However, they are expensive to produce and this restricts their availability to patients; health authorities sometimes cannot afford the costs of these therapies. Lowering production costs may increase access to potentially life-saving treatments. Through synthetic cell bioengineering, we are developing novel approaches to improve production of therapeutic proteins. One of our strategies is to manipulate tRNA expression to enhance translation of recombinant products, tailoring cells to match tRNA supply to specific demands. We aim to reduce costs and thereby increase availability to patients of therapeutics that are currently prohibitively expensive.
As populations increase, the need to improve crop yields is becoming increasingly urgent. Levels of tRNA can strongly impact on growth by influencing rates of protein synthesis, but little is known about how tRNA expression is controlled in plants. We are exploring tRNA control in Arabidopsis and in rice, to determine whether crop production might benefit from raising tRNA expression.
Varshney, D., Vavrova-Anderson, J., Oler, A. J., Cowling, V. H., Cairns, B. R. and White, R. J. (2015) SINE transcription by RNA polymerase III is suppressed by histone methylation but not DNA methylation. Nature Comms. Doi: 10.1038/ncomms7569
Petrie, J. L., Swan, C., Ingram, R. M., Frame, F. M., Collins, A. T., Dumay-Odelot, H., Teichmann, M., Maitland, N. J. and White, R. J. (2019) Effects on prostate cancer cells of targeting RNA polymerase III. Nucleic Acids Res. 47, 3937-3956.
My expertise is in mammalian gene expression and how this goes awry in cancer. These are the subjects that I enjoy teaching.
I run the new Cancer Cell and Molecular Biology module, designed for biochemists, molecular cell biologists and biomedical scientists who are interested in learning more about oncogenes and tumour suppressors and how these impact on cancer. It presents general principles and key molecules, describing how they achieve their functions at cell and molecular levels. All stages are illustrated with examples of particular interest and importance. Therapeutic targets for the treatment of cancer are considered. Experiments from cancer-related research papers are examined in detail to provide training in data interpretation.
Stage 1 tutorials concentrate on the biochemistry of proteins and nucleic acids. They include independent research into post-translational modifications and genetic diseases, followed by presentations. Stage 2 tutorials focus on transcriptional regulation. They involve reading and discussing primary research papers, with emphasis on experimental techniques. Each student chooses a transcription regulator that is implicated in human disease and uses this as subject for an essay and presentation.
Maf1 is an evolutionarily-conserved transcription factor that binds and regulates pol III to control the synthesis of noncoding RNAs such as tRNA. In yeast, loss of Maf1 undermines the response to diverse stress conditions. In fruitflies, Maf1 depletion enhances larval growth and development. My projects investigate if Maf1 affects how plants respond to stress. Wild-type and Maf1 mutant plants are grown under various stressful conditions and carefully monitored for any effects of the mutations on the rate of growth and development.