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Nonsense mediated mRNA decay in plants

Reference	BB/E001823/1
Principal Investigator / Supervisor	Professor Brendan Davies
Co-Investigators / Co-Supervisors
Institution	University of Leeds
Department	Ctr for Plant Sciences
Funding type	Research
Value (£)	259,285
Status	Completed
Type	Research Grant
Start date	01/10/2006
End date	30/09/2009
Duration	36 months

Abstract

Eukaryotes have the intriguing ability to detect mRNA that could encode truncated protein products and target that mRNA for destruction. This is nonsense-mediated mRNA decay (NMD). Although NMD is often thought of as a mechanism to escape the deleterious effects of mutations, it also has a wider role in gene regulation. Analyses in several organisms have shown that more than 10% of genes are subject to regulation of mRNA levels by the NMD machinery. Our understanding of NMD comes from several different model organisms. These studies have implicated a largely overlapping set of conserved genes in the NMD process. Surprisingly, major differences have been discovered between the implementation of the NMD mechanism in these models. In mammals, NMD is triggered by the identification of an inappropriately positioned termination codon in the mRNA. mRNA is marked by a complex (the exon junction complex -EJC) that indicates the positions where introns were removed. Since authentic termination codons are usually found in the final exon, it would be unexpected for an EJC to be present downstream of a termination codon. Therefore if a ribosome meets a termination codon and detects a downstream EJC, the termination codon is considered premature and the mRNA is destroyed. The use of intron position to establish the validity of a stop codon means that monoexonic genes escape the surveillance process. This is not the case in Drosophila or plants; which suggests that different mechanisms are used. Like mammals, Drosophila has an EJC, but the EJC appears not to be involved in NMD. Little is known about NMD in plants and we have accumulated a great deal of background data (see case for support) and are now at the point where we can use our NMD mutants to investigate the mechanism(s) of plant NMD. This project will result in NMD in plants being understood to a greater degree than is currently the case and this will allow the first comparisons of NMD in plants with other organisms.

Summary

Genes contain the information necessary to make the proteins that make cells and make them work. This information is carried from the points of storage (DNA) to the points at which it is used to make specific proteins by a molecule called messenger RNA (mRNA). Despite this information transfer being a relatively accurate process, mistakes are made. DNA rearranges, mutations accumulate and errors are made in interconverting the information. Some of these errors could fool the cell into making incorrect proteins, which will be truncated variants of the correct protein. Unfortunately, such aberrant proteins often have the ability to compete with the normal proteins and create havoc with the correct functioning of cellular processes. Truncated proteins are therefore potentially very dangerous for the organism and it would be an advantage to the cell to prevent them from being made. All eukaryotes have mechanisms to identify and destroy aberrant mRNAs which might encode truncated protein products. The mechanisms are known as nonsense-mediated mRNA decay (NMD) and this proposal seeks to understand NMD in plants. It is not a trivial task for a cell to recognise an mRNA which might encode an incorrect protein and how cells manage this feat is of great topical interest. In essence would like to understand how a plant distinguishes 'good' mRNA from 'bad' mRNA. It is important to study NMD in plants for three main reasons. Firstly, although NMD has been well studied in mammals, worms, flies and yeast, major differences in the mechanism of NMD have been discovered in these model organisms. For example, in mammals it appears that splicing (joining together bits of mRNA) is essential for NMD to recognise aberrant mRNA, because a protein complex (called the EJC) is added to the mRNA to mark the splice points and to provide fixed reference points for the NMD mechanism to screen for errors. As a result of this, the NMD mechanism appears not to work on mammalian mRNAs that are notspliced. However, most yeast (S. cereviseae) mRNAs are not spliced, so a splicing-dependent NMD system would be almost useless. Consequently, yeast uses a different method to identify aberrant mRNAs. Flies have both lots of spliced genes and EJC proteins, but NMD is independent of the EJC in flies. We have almost no idea about NMD in plants. Unlike in mammals, there is evidence that unspliced mRNAs trigger NMD in plants, showing that although other systems can provide a framework for examining NMD, we need to define the rules independently. There is no set of consensus rules that we can apply to plant NMD. Secondly, it is becoming increasingly obvious that the NMD mechanism does not solely exist to weed out bad mRNA. Research in mammals and yeast has shown that the NMD mechanism actually represents a global system of gene expression and that more than 10% of the genes in the cell are under the control of this mechanism. Once again we have no idea whether this will be true for plants or whether overlapping sets of genes will be found to be controlled by NMD in plants and other organisms. Finally, there is some evidence that in worms the NMD mechanism is linked to another important method to regulate gene expression, RNAi. RNAi can be used to downregulate gene expression in several model organisms, including plants. We have evidence that plants which are defective in the NMD process are also deficient in RNAi. We need to explore the link between these two methods of regulatione where the two processes intersect. It will also be very interesting to see what effect is observed following mutagenesis on plants lacking NMD. In such plants one might expect to see a host of phenotypic effects, resulting from the expression of truncated proteins, that would be suppressed in normal plants.

Committee	Closed Committee - Genes & Developmental Biology (GDB)
Research Topics	Plant Science
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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