PhD: exploring the role of arginine methylation for cancer development

Dynamic regulation of protein function via post-translational modifications is critical for nearly all cellular processes. Whilst this has long been appreciated for protein phosphorylation, it is becoming increasingly apparent that other less-well charicterised protein modifications are equally important. Indeed, deregulation of enzymes that catalyse these reactions are known to contribute to human diseases, including cancer.

One such modification is arginine methylation. Surprisingly, although arginine methylation was discovered more than 40 years ago, it is only with the recent identification of the enzymes that catalyse these reactions, PRMTs, that we are starting to understand the significance of arginine methylation for cellular processes. Key to this, has been the identification of proteins targeted for methylation. Accordingly, our group and others have shown that PRMT-mediated methylation of proteins regulates a number of crucial cellular processes including epigenetic-mediated gene expression, transcription factor co-activation, mRNA splicing, signalling, and the DNA damage response, and that this regulates cellular survival, proliferation, genome stability and cellular reprogramming.

Interestingly, many cancers display elevated expression and/or activity of PRMTs, and it is becoming widely appreciated that aberrant arginine methylation contribute to cancer pathogenesis. Because of this, a number of major pharmaceutical companies are activity developing compounds that specifically inhibit PRMTs as a novel way in which to treat cancer. However, if PRMT inhibitors are to be a real clinical success, it is important that we fully understand the role of these enzymes for oncogenesis and malignant progression. Focusing on solid cancers, my laboratory uses a range of methodologies to address these questions, including protein biochemistry, gene knockout and RNA interference in human cancer cell lines, in vitro cancer models, in vivo animal models and patient-derived tumour material. This PhD project will further examine now PRMTs drive tumourigenesis in an effort to validate drug targeting of these enzymes for cancer therapy.

For further information please contact Dr. Clare Davies: c.c.davies@bham.ac.uk

References

1. Davies, C. C., Chakraborty, A., Diefenbacher, M. E., Skehel, M. & Behrens, A. Arginine methylation of the c-Jun coactivator RACO-1 is required for c-Jun/AP-1 activation. EMBO J (2013). doi:10.1038/emboj.2013.98
2. Clarke, T. L. et al. PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination. Mol Cell (2017). doi:10.1016/j.molcel.2017.01.019
3. Yang, Y. & Bedford, M. T. Protein arginine methyltransferases and cancer. Nat Rev Cancer 13, 37–50 (2013).
4. Blanc, R. S. & Richard, S. Arginine Methylation: The Coming of Age. Mol Cell 65, 8–24 (2017).