Zusammenfassung
Eukaryotic cells have evolved elaborate mRNA quality control (surveillance) mechanisms to ensure that only fully processed and error-free mRNAs are translated. These quality control mechanisms operate in both the nucleus and the cytoplasm. For instance, in the nucleus, improperly processed mRNAs are degraded before they are transported to the cytoplasm (for review, see Fasken and Corbett 2005). In the cytoplasm, surveillance pathways assess the translatability of the mRNA and degrade any that have no translation termination codons (nonstop-mediated mRNA decay, NSD) or nonsense codons (nonsense-mediated mRNA decay, NMD), thereby preventing the accumulation of potentially toxic aberrant proteins (for review, see Conti and Izaurralde 2005; Fasken and Corbett 2005; Lejeune and Maquat 2005).
NMD is one of the best characterized mRNA surveillance pathways. Its importance as a protective surveillance mechanism is underscored by the fact that ∼30% of inherited genetic disorders are caused by nonsense mutations or frameshifts, which generate nonsense codons (for review, see Frischmeyer and Dietz 1999; Holbrook et al. 2004). Transcripts derived from the mutant alleles are degraded by NMD, leading in general to a recessive mode of inheritance.
NMD not only rids the cell of mRNAs containing premature translation termination codons (PTCs or nonsense codons) as a result of mutations or errors in transcription or mRNA processing, but also regulates the expression of naturally occurring transcripts that represent ∼10% of the transcriptome in yeast, Drosophila, and human cells (Lelivelt and Culbertson 1999; He et al. 2003; Mendell et al. 2004; Rehwinkel et al. 2005). In this way, NMD plays a role in biological processes as diverse as telomere maintenance, transcription, cell proliferation, cell cycle, cellular transport and organization, and metabolism. A deeper understanding of the mechanism underlying this pathway is therefore of critical importance.
