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Impact of mRNA mistranslation on cell degeneration and evolution
Coordinator - Manuel Santos
Programme - POCI
Execution dates - 2005-09-01 - 2008-08-31 (36 Months)
Funding Entity - FCT
Funding for CESAM - 94717 €
Total Funding - 94717 €
Proponent Institution - Universidade de Aveiro

mRNA misreading is an intrinsic feature of prokaryotic and eukaryotic cells. Under normal growth conditions, the ribosome decodes mRNA at high speed with low error. This is guarantied by a number of translational factors, namely the ribosome, elongation and termination factors (Efs and RFs), aminoacyl-tRNA synthetases (aaRSs) and RNA modifying enzymes. Among these factors, aaRS and tRNAs play important roles in mRNA decoding fidelity as they are involved in two critical steps of mRNA translation: amino acid transfer and codon decoding in the ribosome. mRNA decoding fidelity is being intensively studied at both biochemical and structural levels and a reasonably good picture of the mechanistic and structural features of the translation apparatus already exists. The ribosome, tRNAs, various aaRSs, RNA modifying enzymes, elongation and termination factors have been crystallized at very high resolution, providing an immense knowledge of the mechanism of protein synthesis at molecular and atomic levels. However, many aspects of protein synthesis fidelity remain obscure or poorly understood. For example, the increase of decoding error during stress, aging and disease development has not yet been properly quantified and the impact of mRNA misreading on cell degeneration and human disease remains an almost unexplored area of research. Nevertheless, several short research reports suggest that mRNA mistranslation is of relevance to autoimmune and neurodegenerative diseases, cancer and aging. The PIs´ laboratory has been working on mRNA decoding for a number of years. Recently, his team has engineered yeast cell lines for studying the effect of mRNA mistranslation on cell degeneration and evolution. These cell lines are highly heterogeneous, have unstable genomes and proteomes and unique gene expression profiles. They also display a number of unique degenerative phenotypes, suggesting that yeast is an excellent experimental model system for studying the effect of mRNA mistranslation on cell degeneration. The existence of misreading phenotypes and the availability of a robust model system amenable to genetic manipulation (yeast) indicate that the role mRNA mistranslation on cell degeneration and evolution can be studied. That such studies are bound to provide important new insight into a biological phenomenon of biomedical relevance, which has been overlooked for many years, prompted the development of this project, which, as far as one is aware, represents the first attempt to evaluate the impact of mRNA decoding error on human disease.

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