Translational Termination and its Regulation by Hydroxylation

Synthesis of proteins is essential in order for cells to grow and divide. Since cancer cells generally grow faster than normal cells they need more protein synthesis. Therefore, protein synthesis could be blocked with drugs in tumour cells as a way of treating cancer.

Our research focuses on an enzyme known as JMJD4. Although this enzyme has links to cancer no one knows if, or how, it might contribute to tumour growth. We have recently discovered that JMJD4 regulates a cellular pathway involved in protein synthesis, and that inhibiting JMJD4 stops the growth of tumour cells in the laboratory.

The research in this proposal aims to understand more about JMJD4 and its role in protein synthesis and cancer. Specifically, we wish to study whether JMJD4, and the pathways it regulates in protein synthesis, are required for tumour growth. We will do this using a mouse cancer model (this will extend our previous experiments using the more artificial laboratory-based approach).

The experiments in this proposal also aim to understand exactly how inhibiting the JMJD4 enzyme affects protein synthesis: We will use an exciting and powerful new technique to accurately pinpoint the position of the protein synthesis machinery on the 'genetic code'. The information from this experiment will help us understand how inhibiting JMJD4 stops the growth of tumour cells. Such information could be used to improve the way in which we target drugs against JMJD4 and protein synthesis in the future.

Finally, our work has identified JMJD4 as a novel enzyme that regulates aspects of protein synthesis and tumour cell growth. It would be very useful to identify other enzymes that regulate protein synthesis in cancer cells to develop new ways of combating cancer. Therefore, the proposal also aims to use a genetic 'screen' to ask which of the all the genes in the human genome control similar aspects of protein synthesis to that regulated by JMJD4.

Deregulated protein synthesis and translational control are crucial aspects of cancer initiation and progression. As such protein translation is attracting increasing interest as a source of novel cancer targets. I have recently discovered that the molecular machinery controlling termination of protein synthesis is targeted by JMJD4, a completely uncharacterised 2-oxoglutarate-dependent oxygenase related to the HIF hydroxylases and JmjC-histone demethylases. I have shown that JMJD4 is overexpressed in tumours and required for the viability of cancer cells. JMJD4 hydroxylates K63 of the translational termination factor eRF1 within a highly conserved functional motif involved in stop-codon recognition: JMJD4 inhibition causes ribosomal readthrough of stop codons. I hypothesise that inhibition of eRF1 hydroxylation causes aberrant protein synthesis, re-expression of nonsense mutated tumour suppressor genes and reduced tumuourigenesis. This proposal aims to test these hypotheses using a multidisciplinary approach with the ultimate aim of validating JMJD4 and the translational termination pathway as a novel and druggable anti-cancer target.

This proposal describes research into the role of JMJD4 and translational termination in cancer, with the aim of validating this understudied biological pathway for further medical research and ultimately clinical translation. Therefore, the ultimate potential beneficiaries of the work are cancer patients because the work could give rise to novel therapeutic strategies for combating their disease. As discussed in the proposal, there is also the possibility that the work could benefit other disease patients, namely those suffering diseases caused by nonsense mutations, such as cystic fibrosis and muscular dystrophy.

Since the proposed research aims to explore a novel fundamental aspect of cell biology, and would therefore be classed as 'basic research', the timescale of potential benefit to patients is several years.