Structural investigation of Sam68-driven transcription/splicing coupling

Alternative RNA splicing is an important event giving rise to the complexity of the proteome observed in humans. Splicing events are highly regulated by splicing factors, and splicing defects often lead to a number of pathologies. A typical example is the splicing factor Sam68, which is found overexpressed in a multitude of cancers. Sam68 plays a role in many biological processes including, but not limited to, splicing and transcriptional events, which result in a plethora of cellular outcomes, such as apoptosis, cell migration and differentiation and spermatogenesis. These events are strenuously modulated by signalling pathways, however the molecular mechanisms governing these regulations remain to be fully elucidated. Sam68 has been show to interact with a number of transcription factors, such as the AR, ZBTB7A, CBP and SND-1. The preliminary aim of this research is to characterise the interaction of Sam68 with transcription factor partners, namely the AR and ZBTB7A, in order to determine the nature of the interaction and its importance in biological processes, with a focus on disease development. Techniques including X-ray crystallography, NMR and cryo-EM will be exploited in order to obtain structural information, with the goal of solving the structure of the hetero-trimeric complex. Alongside this, identification of small compounds, perturbing these interactions, will be pursued with hope of characterising novel drugs affecting the oncogenic role of Sam68.