SCHOOL OF BIOCHEMISTRY
Research
Research groups
Research Groups
Kevin Gaston
Reader
+44 (0)117 33 12157 (tel)
+44 (0)117 33 12168 (fax)
kevin.gaston@bristol.ac.uk
Research
Gene regulation
My group is interested in the regulation of gene expression. The recognition of specific DNA sequences by transcription factors is often the first step in the regulation of gene expression. We are studying two transcription factors that bind to DNA using two very different structural motifs: the papillomavirus E2 protein and the homeodomain protein PRH. We hope that our work will help us to understand the mechanisms that these proteins use to find their target genes and control gene expression.
Partial co-localisation of PRH and the corepressor TLE
The PRH protein
The proline-rich homeodomain protein (PRH aka HHex) is an essential regulator of cell differentiation and cell proliferation in the embryo and in the adult. PRH binds to DNA and represses transcription by blocking the access of the basal transcription machinery and also by recruiting the co-repressor protein TLE. Our recent work has shown that PRH forms oligomeric assemblies in vitro and in cells. We are currently investigating the structure of these assemblies and the role that oligomerisation plays in the control of gene expression by PRH.
In collaboration with Dr Sheela Jayaraman (University of Birmingham, UK) we have shown that PRH coordinately regulates the expression of several genes that are important in cell survival. We are currently studying how PRH regulates the expression of the gene encoding vascular endothelial growth factor and the consequences that this regulation has for cell growth.
The E2 DNA binding domain bound to DNA
The E2 proteins
The papillomavirus E2 proteins are an excellent model system in which to study DNA-protein interactions. Members of the E2 class of DNA binding proteins regulate human papillomavirus (HPV) gene expression and are required for HPV replication. Other members of this class of DNA binding proteins are required for the replication of Epstein-Barr virus. Study of these proteins has provided several insights into how transcription factors find their binding sites and regulate gene expression. These viruses are also the causative agents of a number of clinically relevant diseases and work in this area has significant potential benefits for human health.
Our recent work has investigated the DNA binding activity of the HPV E2 proteins and their effects on gene expression and cell survival. Most recently and in collaboration with the group led by Professor Leo Brady, we have determined the structure of the HPV 6 E2 DNA binding domain bound to DNA and shown that the binding of this protein to DNA is highly sensitive to DNA conformation.
Group
Karen Campos, Kerry Wadey, Anya Sawasdichai and Yusra Siddiqui .
Recent publications
Brown, C., Campos Leon, K., Strickland, M., Williams, C., Fairweather, V., Brady, R. L., Crump, M. P., and Gaston, K. (2011) Protein flexibility directs DNA recognition by the papillomavirus E2 proteins. Nucleic Acids Research, 39: 2969-80.
Soufi, A., Sawasdichai, A., Dafforn, T., Smith, C., Jayaraman, P.S., and Gaston, K (2010) DNA compaction by the higher-order assembly of Proline-Rich Homeodomain protein oligomers. Nucleic Acids Research, 38:7513-7525.
Noy, P., Williams, H., Sawasdichai, A., Gaston, K., and Jayaraman P.S. PRH/HHex controls cell survival through coordinate transcriptional regulation of VEGF signalling. (2010) Molecular and Cellular Biology, 30:2120-34.
Williams, H., Jayaraman, P.S., and Gaston K. (2008) DNA wrapping and distortion by an oligomeric homeodomain protein. Journal of Molecular Biology, 383: 10-23.