The steady-state abundance of eukaryotic mRNAs is dictated by the relative rates of their synthesis and degradation. While we know a great deal about molecular mechanisms of transcriptional control, our understanding of mRNA degradation is sketchy by comparison. mRNA stability is an important control point for both constitutive and regulated gene expression. We will investigate C. elegans genes required for mRNA decay. Messenger RNAs that contain premature stop codons are degraded more rapidly than their wild-type counterparts, a phenomenon termed """"""""nonsense-mediated mRNA decay"""""""" (NMD) or """"""""mRNA surveillance"""""""". NMD occurs in all eukaryotes tested, and its action has a substantial impact on human genetic disease. Approximately one third of inherited diseases are due to nonsense or frameshift mutations. NMD modifies many disease phenotypes by affecting abundance of the mutant mRNA. Disease severity often reflects sensitivity of the mutant mRNA to NMD. Loss-of-function mutations affecting any of eight C. elegans genes (smg-1 through smg-8) eliminate NMD. We will study genetic and molecular properties of NMD using these mutants. Our work falls into two broad categories: (1) investigating the molecular mechanisms of NMD; and (2) investigating the biological function of NMD in wild-type animals. Our work is designed to answer two general questions: With what do the SMG proteins interact and how do they regulate mRNA degradation? What mRNAs of wild-type animals are degraded by NMD? Our methods combine genetic, molecular, and biochemical investigations of smg genes and their encoded proteins. Our long-range goals are to understand the molecular mechanisms of mRNA turnover and the biological roles of NMD. Our experiments contribute to these goals by identifying proteins that are required for NMD, by describing their activities in vivo, and by investigating the role of NMD during normal growth and development. ? ?
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| LeGendre, Jacqueline Baca; Campbell, Zachary T; Kroll-Conner, Peggy et al. (2013) RNA targets and specificity of Staufen, a double-stranded RNA-binding protein in Caenorhabditis elegans. J Biol Chem 288:2532-45 |
| Izumi, Natsuko; Yamashita, Akio; Iwamatsu, Akihiro et al. (2010) AAA+ proteins RUVBL1 and RUVBL2 coordinate PIKK activity and function in nonsense-mediated mRNA decay. Sci Signal 3:ra27 |
| Hubert, Amy; Anderson, Philip (2009) The C. elegans sex determination gene laf-1 encodes a putative DEAD-box RNA helicase. Dev Biol 330:358-67 |
| Squirrell, Jayne M; Eggers, Zachary T; Luedke, Nancy et al. (2006) CAR-1, a protein that localizes with the mRNA decapping component DCAP-1, is required for cytokinesis and ER organization in Caenorhabditis elegans embryos. Mol Biol Cell 17:336-44 |
