Investigation of nonsense mediated mRNA decay (NMD) mechanisms

Gene expression typically refers to the process that leads from gene to functional protein and involves transcription of DNA into mRNA and translation of the transcript into protein. The process is particularly complex in eukaryotes (the group of organisms that, like yeast and humans but unlike bacteria, are made of cells which have the chromosomal DNA enclosed within a membrane-bounded nucleus); in these cells the primary mRNA transcript needs to undergo several modifications (pre-mRNA processing) in the nucleus and quality control steps before it is efficiently translated in the cytoplasm. Mutations or environmental conditions that reduce the accuracy of this process can lead to several human diseases. The research in the main applicant's laboratory focuses on understanding nonsense mediated mRNA decay (NMD), one of the more important cellular quality-control processes that removes abnormal mRNAs that could potentially encode for toxic truncated proteins. NMD also has a central role in modulating the expression of many normal genes and since NMD is interlinked with essentially all other processes in gene expression, a full understanding of this insufficiently understood mechanism will greatly advance our understanding of the fundamental question of how genes are correctly expressed in cells.

Although this research is aimed at understanding fundamental molecular biology so as to advance fundamental knowledge, long term it may also have an economic impact on society. It can for example advance our understanding of the molecular mechanisms that cause certain human diseases and possibly offer new treatments. Specifically, NMD is a promising drug target for a class of mutations that are linked to human diseases. A USA pharmaceutical company (PTC Therapeutics- www.ptcbio.com) reported that some forms of Duchenne muscular dystrophy (DMD) and possibly other human diseases caused by mutations that block mRNA translation prematurely, can be treated with a drug that emerged from NMD studies. This drug (Ataluren, trade name Translarna) has been recently approved by the European Medicine Agency for treating DMD and could shortly be available in the UK.

Nonsense mediated mRNA decay (NMD) is an evolution conserved translation-dependent mechanism that degrades abnormal mRNAs which carry either a premature stop codon (PTC) or other NMD-inducing features such as an abnormal long 3' UTR. Although NMD was initially described as a specialized mRNA surveillance mechanism that prevents accumulation of abnormal mRNAs coding for potentially toxic truncated peptides, a number of later studies indicate that NMD affects the expression of a large fraction of the genome from yeast to human, for example by targeting aberrantly spliced transcripts which harbor an NMD-inducing PTC. It therefore appears that NMD has an important global function in fine-tuning eukaryotic gene expression. While it is well established that NMD is coupled to premature translation termination, the mechanism by which some but not other PTCs cause NMD is not sufficiently understood in any organism. Moreover, pre-mRNA splicing appears to be involved in this process across organisms, yet current models cannot account for many features of this still unsolved interconnection between pre-mRNA processing in the nucleus and translation in the cytoplasm. This research aims to understand the basic NMD mechanism in Schizosaccharomyces pombe, which as demonstrated by earlier studies and extensive preliminary observations in the main applicant's laboratory, is a promising experimental system to gain an alternative vantage point that could radically change our current understanding of NMD and unveil the mechanism of its links to translation, pre-mRNA processing and mRNA turnover.

The research we have proposed is primarily driven by the quest to fully understand a specific cellular mechanism in an amenable experimental organism. While we cannot precisely predict what the benefit of this specific research will be to society, most of what is known about human health and diseases is built on fundamental knowledge of how genes and cells work. In the long term the knowledge that we will gain might help in our understanding of certain disease processes and suggest new treatments. The particular cellular mechanism we are studying, nonsense mediated mRNA decay (NMD) is a promising drug target for genetic diseases that are caused by nonsense mutations. The drug Ataluren (tradename Translarna) has been recently approved by the European Medicine Agency for treating Duchenne muscular dystrophy and could shortly be available in the UK. This drug is also in clinical trials for other diseases caused by this class of mutations (http://www.ptcbio.com/ataluren). PTC Therapeutics, the company that discovered Ataluren, was started by Dr Stuart Peltz and others following up on their pioneering work in characterising NMD in budding yeast. The mechanism of action of Ataluren remains controversial. It is likely that the knowledge that will emerge from our research into the basic NMD mechanism will provide insights into what might be its precise molecular target. This could therefore be of interest to pharmaceutical companies as they seek ways of addressing debilitating diseases such as Duchenne muscular dystrophy.

We believe that an effective way to convey the importance of basic science is to engage with the local public and, perhaps more importantly, with schools. The link between NMD and disease is a way of highlighting the importance of studying fundamental biological processes. We will communicate with the public through outreach activities, such as hosting pupils from local schools in our laboratories and organizing public exhibits at our yearly university Community Day. We will also publish the results of our research in prominent open-access journals, which as well as a means of communication is also the way we can contribute to the prestige of UK science and the educational sector, which are major assets and important economy-drivers in this country.