Abstract
Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that degrades mRNAs harboring premature termination codons (PTCs). We have conducted a genome-wide RNAi screen in Caenorhabditis elegans that resulted in the identification of five novel NMD genes that are conserved throughout evolution. Two of their human homologs, GNL2 (ngp-1) and SEC13 (npp-20), are also required for NMD in human cells. We also show that the C. elegans gene noah-2, which is present in Drosophila melanogaster but absent in humans, is an NMD factor in fruit flies. Altogether, these data identify novel NMD factors that are conserved throughout evolution, highlighting the complexity of the NMD pathway and suggesting that yet uncovered novel factors may act to regulate this process.
Highlights
The Nonsense-mediated mRNA decay (NMD) pathway targets mRNAs harboring premature termination codons (PTCs) for degradation, and regulates the stability of a wide array of endogenous transcripts [reviewed by 1–3]
Our previous RNAi screen in C. elegans led to the identification of smgl-1/NBAS and smgl-2/DHX34 that act in NMD in nematodes and vertebrates [6,12]
We fed PTCxi animals empty RNAi vector, which had no effect on the level of GFP expression (Fig 2A, panel I), whereas inactivation of the core NMD factor, SMG-2/UPF1, which induced strong GFP expression, was used as a positive control (Fig 2A, panel II)
Summary
The NMD pathway targets mRNAs harboring premature termination codons (PTCs) for degradation, and regulates the stability of a wide array of endogenous transcripts [reviewed by 1–3]. A similar approach in Saccharomyces cerevisiae identified three NMD genes, UPF1-3 (for up-frameshift), that are orthologs of C. elegans smg-2, smg-3 and smg-4, respectively. A genome-wide RNAi screen in C. elegans identified two additional NMD factors that are conserved throughout evolution and, unlike the core smg-1-7 genes, are essential for embryonic development [6]. They were termed smgl-1 and smgl-2 (for smg-lethal-1 and 2, respectively). Their human homologs, NBAS (for neuroblastoma amplified sequence) and DHX34, act in concert with core NMD factors to coregulate a large number of endogenous RNA targets [7]
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