Nonsense Mediated mRNA Decay Pathway

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Messenger RNA (mRNA) degradation is a process that plays an important role in the regulation of gene expression. mRNA decay rates vary greatly and can be modulated in response to environmental signals. Many studies have demonstrated that mRNA turnover an be linked to translation. One pathway that has been extensively investigated and clearly exemplified the link between translation and mRNA turnover is the nonsense-mediated mRNA decay pathway (NMD). Nonsense mutations in a gene can accelerate the decay of the mRNA transcribed from that gene. The NMD pathway in eukaryotes is a conserved mechanism that rids cells of faulty gene products that can interfere with cell function. Approximately fifteen- to thirty percent of all genetic disorders arise as a consequence of nonsense mutations. Therefore, understanding how this pathway functions should e able to lead to treatments for a subset of all patients suffering from genetic disorders in which there is presently no cure, having been investigating both the cis- and trans-acting factors involved in regulating the NMD pathway. Mutations in the UPF1/MOF4/IFS2, UPF2/NMD/SUA/IFS1, UPF3/SUA6, MOF2/SU11, MOF5, and MOF8 genes result in an increased accumulation of nonsense-containing mRNAs while having no effect on the abundance of most wild-type transcripts. These studies also demonstrated a link between multiple process of translation and decay. In particular, we have shown that there is a cross-talk between the processes of translation termination, degradation of transcripts harboring premature translation termination, and ribosomal frameshifting. Based on these observations, we have hypothesized the presence of a "surveillance complex" that monitors these processes and increases their fidelity. We have also shown that the surveillance complex recognizes an RNA as aberrant by interacting with RNA binding proteins 3' of the termination codon. Based on these studies, we have proposed a model that suggests that the surveillance complex assesses translation termination by monitoring the transition of an RNP as it is converted from a nuclear to a cytoplasmic form during the initial rounds of translation. The goals of the experiments in this grant proposal are to investigate the sequences and factors involved in the NMD pathway in order to dissect its mechanism and how it is regulated.