GENETIC &MOLECULAR STUDIES OF NEMATODE MRNA DEGRADATION

University Of Wisconsin Madison, Madison WI

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Abstract

The steady-state levels of eukaryotic mRNAs are dictated by their relative rates of 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. Decay of individual mRNAs is determined by the interplay of specific cis-acting elements and trans-acting factors. Cis-acting elements control decay of mRNAs in which they reside, while trans-acting factors interact with those elements and with other cellular processes, especially the translational apparatus. Numerous cis-acting sequences important for mRNA decay have been defined, but how these elements, together with their trans-acting factors, accomplish selective mRNA turnover is poorly understood. Most mRNA turnover is intimately coupled to translation. This is particularly clear in the case of nonsense mutant mRNAs. mRNAs that contain premature stop codons are unstable in all eukaryotes tested, including humans. We will study this phenomenon, termed "nonsense-mediated mRNA decay" (NMD) in the nematode Caenorhabditis elegans. Loss-of-function mutations affecting any of seven different genes (smg-1 through smg-7) eliminate NMD throughout the animal. Thus, smg genes encode trans-acting factors required for NMD. Our work is designed to answer three general questions: What are the smg gene products? With what do they interact? What are the natural targets of NMD in wild-type nematodes? 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, describing their biochemical associations in the cell, and investigating the role of smg genes in normal gene expression. NMD is a universal phenomenon and contributes to the severity of certain human genetic diseases. Understanding the mechanisms of NMD and the functions of smg genes in C. elegans will contribute to understanding the etiology of these and other diseases.