Exploiting epigenetic control to develop novel cancer drugs

Project Code: 

To design effective cancer therapies, it is essential to decipher the molecular details and interplay between the key pathways that control proliferation, and identify the molecular defects that occur in cancer. The retinoblastoma protein pRb is a key tumour suppressor that acts in a negative way to control proliferation, and is frequently mutated in tumour cells. Transcription factor E2F is a critical target through which pRb influences proliferation. Our work is focussed on the molecular mechanisms which control E2F activity, and how they become de-regulated in cancer. The epigenetic mark, arginine methylation, acts as a crucial cancer-relevant mechanism by targeting E2F activity, which then enables cells to remain in their proliferative cycle.  The goal of this project is to gain a mechanistic understanding of how PRMT5 influences E2F activity, focussing principally on its genome-wide effects. We will explore the genome-wide chromatin-association of E2F using ChIP-Seq, and the impact of PRMT5 by treating cells with small molecules which block its enzyme activity in cells. The genome-wide role of PRMT5 in normal and cancer cells will be compared, across a range of different tumours, with the ultimate aim of leveraging the information to identify tumours that respond favourably to PRMT5 inhibition. Secondary supervision will be provided by Simon Carr.

  1. 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
  2. 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
  3. Ghari, F., Quirke, A.M., Munro, S., Picaud, S., FillipakopoulosP, McGouran, J., Subramanian, V., Thompson, P., Venables, P., Kessler, B and La Thangue, N.B.  (2016) Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response. Science Advances 5,2 e1501257

  4. Zheng, S., Moehlenbrink, J., Lu, Y.C., Zalmas, L.P., Sagum, C.A., Carr, S., McGouran, J.F., Alexander, L., Fedorov, O., Munro, S., Kessler, B., Bedford, M.T., Yu, Q. and La Thangue, N.B. (2013) Arginine methylation-dependent reader-writer interplay governs growth control by E2F-1. Molecular Cell, 52 (1) 37-51

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