Grant: Operating Grant

Gene expression plays a critical role in regulating and modifying various cellular functions, which impact on processes such as development and homeostasis. In eukaryotic cells, gene activation begins in the nucleus, where DNA is transcribed into messenger RNA (mRNA). After the mRNA is processed it is exported into the cytoplasm where it is translated into protein. Previously, I discovered that a subset mRNAs encoding secreted and mitochondrial proteins are exported by a specialized mRNA nuclear export pathway. These mRNAs contain an element, the SSCR/MSCR, that is found within the open reading frame and is translated in the cytoplasm into a cleavable leader peptide that targets the newly made protein for secretion or to an organelle. I discovered that SSCRs and MSCRs derived from mammalian genes not only encode targeting peptides, but also act as RNA elements that promote mRNA nuclear export. In humans, approximately 10 to 15% of all genes have this export element. We believe that this export pathway evolved only recently as the sequence characteristics that promote export is only seen in vertebrate SSCRs and MSCRs. In unpublished work, I found that at least one model SSCR binds to a set of nuclear proteins that have been implicated in nuclear export and may regulate mRNA localization in the cytoplasm. In this proposal I will describe my plans for investigating the molecular mechanisms responsible for the specialized export of mRNA encoding secreted and mitochondrial proteins. In the process I will gain a deeper understanding of the role of this mRNA export pathway in the production and function of newly synthesized proteins.