mRNA surveillance mitigates genetic dominance in Caenorhabditis elegans

Nonsense mutant mRNAs are unstable in all eucaryotes tested, a phenomenon t ermed nonsense-mediated mRNA decay (NMD) or mRNA surveillance. Functions of the seven sung genes are required for mRNA surveillance in Caenorhabditis elegans. In Smg(+) genetic backgrounds, nonsense-mutant mRNAs are unstable, while in Smg(-) backgrounds such mRNAs are stable. Previous work has demon strated that the elevated level of nonsense-mutant mRNAs in Smg(-) animals can influence the phenotypic effects of heterozygous nonsense mutations. Ce rtain nonsense alleles of a muscle myosin heavy chain gene are recessive in Smg(+) backgrounds but strongly dominant in Smg(-) backgrounds. Such allel es probably express disruptive myosin polypeptide fragments whose abundance is elevated in sung mutants due to elevation of mRNA levels. We report her e that mutations in a variety of C. elegans genes are strongly dominant in Smg(-), but recessive or only weakly dominant in Smg(+) backgrounds. We iso lated 32 dominant visible mutations in a Smg(-) genetic background and test ed whether their dominance requires a functional NMD system. The dominance of 21 of these mutations is influenced by NMD. We demonstrate, furthermore, that in the case of myosin, the dominant-negative effects of nonsense alle les are likely to be due to expression of N-terminal nonsense-fragment poly peptides, not to mistranslation of the nonsense codons. mRNA surveillance, therefore, may mitigate potentially deleterious effects of many heterozygou s germline and somatic nonsense or frameshift mutations. We also provide ev idence that smg-6, a gene previously identified as being required for NMD, performs essential function(s) in addition to its role in NMD.