Podcast: Targeting epigenetics to treat cancer

Transcription in eukaryotic cells is a tightly regulated process, which depends on the spatial and transient formation of non-covalent protein complexes mediated by post-translational modifications, such as lysine acetylation. Members of the bromo and extra-terminal (BET) family play key roles in this assembly process. BET family members belong to the family of bromodomains the only known protein recognition module that selectively recognizes and binds ε-N-acetylated lysine (Kac). Dysfunction of the transcription elongation process leads to the development of aggressive cancers and disease. The specific substrates, links to cellular signalling and mode of action of these modular domains remain elusive; however their dysfunction has been linked to disease. They have been identified as oncogenic fusions in aggressive carcinomas; drive the expression of oncogenes such a c-Myc and play essential roles in viral recruitment and viral genome segregation. Importantly, we and others have demonstrated that it is possible to inhibit their function by targeting their mechanism of action resulting in dramatic effects in disease, leading to potential therapies. This novel targeting mechanism based on the inhibition of protein interactions initiated by reader domains of chromatin modifications needs to be further explored in order to understand and explain transcription initiation.

We aim to address the structural and functional role of BET bromodomains in transcription initiation and the implications of dysfunctional BET bromodomains in disease. For instance BETs are found fused to the NUT (nuclear protein in testis) protein driving the growth of a rare subtype of squamous cell carcinoma or they are associated to viral oncoproteins. We employ high throughput structural biology techniques in order to study BET bromodomains, seeking to establish an interaction map with their substrates, understand the molecular details of substrate interactions, explain synergy between multiple BET bromodomain modules, explore the molecular and structural basis for the recruitment of the positive transcription elongation factor b (P-TEFb) by BET proteins to chromatin, structurally characterize their oncogenic fusions to NUT and probe the molecular and structural basis of their interactions with viral oncoproteins.