Translating epigenetic control into novel cancer therapeutics
Nominating Supervisor: Prof Nick La Thangue
Second Supervisor: Prof David Kerr
The retinoblastoma protein pRb is a key tumour suppressor that governs fundamental mechanisms in the G1 to S phase transition of the cell cycle. Its activity is deregulated in the vast majority of human tumours, and E2F transcription factors are recognised to be the major transcriptional hub under pRb control. Our work is focussed on the uncovering new mechanisms and pathways which link pRb and E2F activity to the complex biological properties of cancer cells, and deploying the information to develop improved or new therapeutic modalities. The epigenetic mark, arginine methylation, is often under abnormal control in cancer where it influences pRb and E2F activity, enabling cancer cells to remain in their proliferative cycle. This is mediated through a novel cancer-relevant mechanism whereby arginine methylation diverts E2F from its established transcriptional role to influence other levels of gene control connected with RNA processing like alternative RNA splicing. The goal of this project is to gain a deep understanding of arginine methylation and its cancer significance, and explore at the global level its impact on gene expression, RNA processing and protein function. A key objective will be to clarify the role of arginine methylation in different types of cancer, to identify the cancers that respond favourably to therapies that target arginine methylation. Ultimately, we will aim to translate the information gained in the laboratory to the clinical setting.
Unique research in cancer biology; internationally competitive projects in cell cycle control and novel platforms for exploring new levels of post-translational control. Productive projects yielding high profile publications. Proven translational capacity. Clinical trials underway with drugs and biomarkers developed in the laboratory. Track record in spinning out companies to leverage academic findings. Continuing collaboration with spin out companies particularly in chemical biology applications to probe cancer-relevant mechanisms.
Munro, S Hookway, E, Floderer, M, Carr, S Konietzny, R, Kessler, B Oppermann, U and La Thangue, N.B (2017) Linker H1 histones direct the genome-wide chromatin-association and facilitate the biological effects of the retinoblastoma tumour suppressor protein. Cell Reports, 11 2193-2201
Olzscha H, Fedorov O, Kessler BM, Knapp S, and La Thangue N.B. (2017) CBP/p300 Bromodomains Regulate Amyloid-like Protein Aggregation upon Aberrant Lysine Acetylation. Cell Chemical Biology. 24(1):9-23
A. P. Roworth, S. M. Carr, G. Liu, W. Barczak, R. L. Miller, S. Munro, A. Kanapin, A. Samsonova, N. B. La Thangue, Arginine methylation expands the regulatory mechanisms and extends the genomic landscape under E2F control. Sci. Adv. 5, eaaw4640 (2019).