Scheme: Wolfson Research Merit Awards
Organisation: University of Leicester
Dates: Aug 2013-Jul 2018
Summary: All cells within an organism contain the same genetic information, yet they have quite different properties and roles depending within which tissue they are located. The differences are determined by which genes are active in a particular cell. When a gene is active it means that the protein encoded by that gene is ‘expressed’ through the processes of transcription and translation.
Genes being inappropriately active or inactive causes many human diseases. This is particularly true of cancers. However, by understanding how genes are regulated, we can intervene using drugs that change patterns of gene expression and in many cases cause the rogue cancer cells to die. The more we understand about how cells regulate gene expression the more chances we have at rational intervention.
Some new drugs that are starting to be used to treat certain kinds of cancer inhibit enzymes called histone deacetylases. These enzymes play an important role in regulating gene expression because they control whether the DNA for a particular gene is wrapped up with histone proteins and hidden from the transcription machinery, or whether the gene is accessible to be transcribed.
Our research concerns understanding how histone deacetylases work. We know that they exist in the cell in the form of large complexes containing many proteins. These proteins help ensure that the enzymes are in the right place at the right time and target the right genes. We are trying to understand how these deacetylase complexes are assembled and how assembly into these complexes controls the activity of the enzymes.
The way we approach this work is to use X-rays to determine the structures of these proteins and their complexes so that we can directly observed how they are put together. We also use state-of-the-art electron microscopes to explore the assembly of some of the larger complexes.