Regulation of Nonsense-Mediated mRNA Decay

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Intellectual Merit: Understanding how genes are turned on and off is a major key to understanding life. There are many levels of gene regulation in biology, such as the decision to copy the DNA into a messenger RNA or the decisions that regulate how much protein is translated from the messenger RNA. This project focuses on another level of gene regulation, i.e. mRNA stability. The longer an mRNA stays around, the more protein can be made from it. Nonsense-mediated mRNA decay (NMD) is a mechanism that controls RNA stability. The NMD degradation pathway depends on the placement of signals in the RNA that stop protein translation; the shorter the protein that is made, the less stable the RNA. One way that mRNAs can gain stop signals is through alternative splicing; approximately one third of the genes that undergo alternative splicing generate an alternative messenger RNA that is preferentially destroyed by the NMD pathway. The main goal of this project is to study the regulation of the NMD pathway using the model organism, Caenorhabditis elegans. Specific aims are: 1) to understand the relationship between alternative splicing and NMD; 2) to identify molecules that control the NMD process; and 3) to probe the relationship between translational state (whether a mRNA is making protein or not) and efficiency of NMD. Because NMD is an important quality control mechanism for RNA in the cell, these studies will make important contributions to our understanding of gene regulation.Broader Impacts: This project will provide training opportunities for both graduate and undergraduate students. The experiments to be conducted in this project are perfect for introducing undergraduates to the excitement of research science. The laboratory has a history of recruiting undergraduates from underrepresented groups and will continue to do so in this project.