PTC Recognition in Human Nonsense-mediated mRNA Decay

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The information that controls the growth and multiplication of cells in our body is contained within the genes of their chromosomes. Most genes direct the transcription of messenger RNAs (mRNAs) in the nucleus of the cell. After the mRNA is transcribed it undergoes further processing in the nucleus, which includes removal of non-coding segments called introns by the process of splicing. Fully processed mRNAs are then exported to the cytoplasm where they serve as templates for production of proteins mediated by the ribosome. Sometimes when mRNAs are processed, mistakes happen that cause the mRNA to encode aberrantly shortened protein products. This can be deleterious to cells, as even small amounts of shortened protein products can in some cases block the process in which the full-length protein normally functions. However, eukaryotic cells have evolved a machinery to identify and degrade such aberrant mRNAs, thus preventing their production of shortened protein products. This machinery is called the nonsense-mediated mRNA decay (NMD) pathway. The mechanism by which the NMD pathway identifies aberrant mRNAs is poorly understood and highly debated. In this project, it will be studied how the NMD machinery cooperates with the ribosome to identify aberrant mRNAs that encode shortened proteins, and how this is influenced by the process of mRNA splicing in the nucleus.This project will train two graduate students, including a female student. In addition, two or three undergraduate students and one or more high-school students will be exposed to biological research. This project is an integral part of the principal investigator's undergraduate and graduate teaching in Molecular Biology at the University of Colorado, Boulder. This project should also generate several reagents that will help other researchers advance this field of research.