The Biology of RNA polymerase III.
RNA polymerase (pol) III transcribes DNA to produce an eclectic mix of short non-coding RNAs, such as tRNA. This transcription is highly regulated. Our research focuses on the molecular mechanisms and functional consequences of pol III regulation during cell differentiation, growth, proliferation and oncogenic transformation. We are 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.
Rapidly growing cells require high rates of transcription by pol III to supply essential RNAs. This is very apparent in cancers, where elevated levels of pol III transcripts are commonly observed. We aim to target pol III as a way to tackle tumour growth.
The gene encoding the pol III-specific transcription factor Brf1 produces one of the most highly overexpressed mRNAs in childhood B-cell acute lymphoblastic leukaemia (B-ALL). The image compares Brf1 mRNA levels in 74 healthy volunteers (left) with levels in 359 children with B-ALL (right). The increase in the leukaemic patients is highly significant (P=3X10-66).
Cells overexpressing a mutant form of the pol III-specific transcription factor Brf1 display frequent nuclear abnormalities. Three examples are shown, with the DNA stained using DAPI.
Fairley, J. A., Mitchell, L. E., Berg, T., Kenneth, N. S., von Schubert, C., Sillje, H. H. W., Medema, R. H., Nigg, E. A. and White, R. J. (2012) Direct regulation of tRNA and 5S rRNA gene transcription by Polo-like kinase 1. Mol. Cell 45, 541-552.
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
My expertise is in mammalian gene expression and how this goes awry in cancer. These are the subjects that I enjoy teaching.
For stage 2, I run the Eukaryotic Gene Expression module. This examines the molecular processes involved in expression of genetic information in eukaryotic cells and how these are regulated, including transcription, splicing, translation.
For stage 3, I run the Transcription and Cancer module, designed for biochemists, molecular cell biologists and biomedical scientists who are interested in learning more about the mechanisms and control of gene transcription in humans and how these impact on cancer. It presents general principles and key molecules, describing how they achieve their functions. All stages are illustrated with examples of particular interest and importance. Transcription and transcription factors are considered as potential therapeutic targets for the treatment of cancer. Experiments from transcription-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 powerpoint 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 powerpoint 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. This project investigates if Maf1 affects how Arabidopsis responds 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.
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