4 Year Wellcome Trust PhD Programme: Functions of SWI/SNF related chromatin remodelling complexes in cancer.

Human genome sequencing has provided a means of identifying genes that contribute to complex diseases such as cancer. A surprising outcome has been the finding that subunits of human SWI/SNF chromatin remodelling complexes are mutated at a frequency of approximately 20% in tumours of all tissues. Interestingly, different subunits of the same complexes are muted in cancers of different tissues. We are taking a range of different approaches to investigate this and PhD projects are possible relating to each of these. We are investigating the extent to which composition of hSWISNF complexes varies in tumour tissue and in cancer cell lines at the protein level using affinity purification and proteomics. We are characterising how the function of hypomorphic complexes is misappropriated in a tissue specific fashion both in tumour tissue and in engineered cell lines. Further mechanistic insight will be gained by studying how different subunits interact using X-link MS, X-ray crystallography and Cryo-EM. We will study how the biochemical activities of the complex are influenced by histone modifications and heterochromatin complexes. Insight into the molecular mechanisms by which defective complexes drive cancer will hopefully provide opportunities to identify vulnerabilities in these cancer types that can be exploited for development of new therapeutics or patient stratification.