ABSTRACT
Loss-of-function mutations affecting seven different genes eliminate nonsense-mediated mRNA decay (NMD) in Caenorhabditis elegans. Three of these genes (smg-2, smg-3, and smg-4) are orthologs of Saccharomyces cerevisiae NM D genes ( UPF1, UPF2, and UPF3, respectively). SMG-2, a central regulator of NM D, undergoes cycles o f reversible phos phorylation, and all other smg genes influence the state of its phosphorylation. SMG-1, SMG-3, and SMG-4 are required to phosphorylate SMG-2, and SMG-3, SMG-6, and SMG-7 are required to dephosphorylate SMG-2. Both the SMG-2 phosphorylation and dephosphorylation steps are required for NM D, but the functions of this posttranslational modification are poorly understood. Smg mutations are allele-specific but not gene-specific modifiers of phenotypes caused by mutations affecting many different genes. NM D lessens the deleterious effects of heterozygous and homozygous nonsense mutations by degrading the affected mRNA. Wild-type C. elegans expresses substantial quantities of mRNAs that contain premature termination codons and are degraded by NM D. These include mRNAs regulated posttranscriptionally by unpro ductive alternative splicing and mRNAs of expressed pseudogenes.
