Grant: Operating Grant

The sequencing of the human genome and the discovery of RNA interference revealed that both mRNA maturation (e.g. Splicing) and stability play much more important roles in the regulation of gene expression than previously predicted. It is now clear that gene expression during development is largely controlled through changes in the splicing and degradation pattern of mRNAs. More interestingly, it has recently been shown that RNAi might be linked to cancer, cardiovascular diseases and DiGeorge syndrome thus linking a possible defect in mRNA decay to human disease. Indeed, we have shown recently that alternative splicing pattern could serve as markers for ovarian and breast cancer. However, despite these exciting findings, there is no systematic effort to demonstrate the overall contribution of RNA metabolism to cell function and link it to human disease. By studying the factors that regulate mRNA response in yeast we will provide the first integrated view of the mechanism controlling conditional mRNA decay in any organism, and will provide a model to test in mammals. On the long term, the result of the proposed studies will help us produce a portrait of how cellular RNA drive cellular phenotypes and lead to human disease. This global understanding of RNA metabolism is expected to generate more precise markers and drug targets for complex human disease like cancer. Meanwhile, the goal of this proposal is to understand the biological function of basic components of the eukaryotic cell.