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Functional genomics of ribosome infidelity phenotypes associated to human diseases
Coordinator - Manuel Santos
Programme - COMPETE
Execution dates - 2010-05-02 - 2013-05-01 (36 Months)
Funding Entity - FCT
Funding for CESAM - 199200 €
Total Funding - 199200 €
Proponent Institution - Universidade de Aveiro


The fidelity of DNA replication, transcription and mRNA translation is critical to homeostasis. These informational processes are not 100% accurate, however low level of error is compatible with life, creates genetic diversity and is evolutionary relevant. Under normal growth conditions, DNA replication, transcription and translation errors are in the order of 10-11, 10-5 and 10-4, respectively. This low error is achieved through various quality control mechanisms involving proofreading during synthesis and post-synthesis error repair systems. Deregulation of DNA repair mechanisms or mutations that affect proofreading by DNA polymerases accelerate mutation rate and are a major cause of human disease, cancer in particular. They also generate hypermutagenesis phenotypes and accelerate evolution of pathogenic traits in various bacterial species, namely E. coli and Salmonella and Staphylococcus. On the other hand, transcriptional and translational errors are poorly understood. However, the sophistication of quality control mechanisms operating at the RNA and protein levels, namely the eukaryotic non-sense mediated mRNA decay pathway (NMD), proteasome, ERAD and autophagy systems, suggest that transcriptional and translational errors are rather important. Indeed, ribosome misreading caused by mutations in ribosomal components, tRNAs, initiation, elongation and termination factors and in genes that encode tRNA and rRNA modifying enzymes are associated with neurodegeneration, cancer and mitochondrial myopathies. The mechanism(s) by which ribosome infidelity (mistranslation) causes these diseases is (are) not yet understood. In this project, we will study the basic biology of ribosome infidelity in yeast and will compare the cellular responses between yeast and mammalian cells. These studies will provide new insight on how eukaryotic cells cope with ribosome infidelity, will identify the main biological processes activated and/or repressed by it and will elucidate how it causes cell degeneration and death. It will also provide the first insight on how different types of human cells respond to ribosome infidelity. Methods to monitor ribosome infidelity in vivo and in vitro will be standardized and new methods to quantify it in vivo will be developed. Since ribosome infidelity has a global impact on cellular processes state of the art mRNA and microRNA profiling, comparative genome analysis on array (aCGH) and Molecular/Cellular Biology methodologies will be integrated to obtain a full picture of its biology. Therefore, this project will make a significant contribution to understand the basic biology of ribosome infidelity and to elucidate how this overlooked biological phenomenon causes human diseases. It will also provide insight on how to develop new screens to identify drugs for human diseases associated with protein misfolding and aggregation. The project will promote RNA biology, Genomics and Molecular Biology in Portugal through direct support of 7 MsC, PhD and Postdoctoral fellows and will be of paramount importance to consolidate the PIs´ research program. The PI spent 10 years in the UK, France and USA, returned to Portugal in 1999 and since then created a dynamic and competitive research laboratory at the University of Aveiro. He was a Wellcome Trust Career Development Fellow and was nominated for an EMBO Young Investigator award in 2001. Over the last 15 years, his research has been funded by prestigious international research funding agencies, namely the Wellcome Trust, EMBO and the Human Frontier Science Program. This allowed him to publish some of his results in high quality journals, namely EMBO J. (IF= (8.67), Genome Research (IF=11.22), Genome Biology (IF = 6.6), Nucleic Acids Research (IF=6.95); Molecular Microbiology (IF=5.5); PNAS (IF=9.6; in press). (PDFs available at http://www.ua.pt/ii/rnomics). Therefore, this project will provide high level training to the next generation of Portuguese scientists.




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