Aberrant termination triggers nonsense-mediated mRNA decay

Amrani, Nadia; Dong, Shuyun; He, Feng; Ganesan, Robin; Ghosh, Shubhendu; Kervestin, Stéphanie; Li, Chunfang; Mangus, David A.; Spatrick, Phyllis; Jacobson, Allan

doi:10.1042/bst0340039

Cited by 68 publications

(58 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alternatively, the "faux 3ЈUTR" model proposes that translation termination at a nonsense codon is intrinsically aberrant, due to the fact that a PTC is not in an appropriate context. In support of this hypothesis, tethering of poly(A)-binding protein in the proximity of a PTC mimicked a normal 3ЈUTR and suppressed NMD (Amrani et al 2004(Amrani et al , 2006. Thus, despite the conservation of the NMD machinery, different mechanisms have evolved to define PTCs and discriminate them from natural stop codons in metazoa (for review, see Conti and Izaurralde 2005).…”

mentioning

confidence: 90%

Mechanistic insights and identification of two novel factors in the C. elegans NMD pathway

Longman¹,

Plasterk²,

Johnstone³

et al. 2007

Genes Dev.

149

187

View full text Add to dashboard Cite

The nonsense-mediated mRNA decay (NMD) pathway selectively degrades mRNAs harboring premature termination codons (PTCs). Seven genes (smg-1-7, for suppressor with morphological effect on genitalia) that are essential for NMD were originally identified in the nematode Caenorhabditis elegans, and orthologs of these genes have been found in several species. Whereas in humans NMD is linked to splicing, PTC definition occurs independently of exon boundaries in Drosophila. Here, we have conducted an analysis of the cis-acting sequences and trans-acting factors that are required for NMD in C. elegans. We show that a PTC codon is defined independently of introns in C. elegans and, consequently, components of the exon junction complex (EJC) are dispensable for NMD. We also show a distance-dependent effect, whereby PTCs that are closer to the 3 end of the mRNA are less sensitive to NMD. We also provide evidence for the existence of previously unidentified components of the NMD pathway that, unlike known smg genes, are essential for viability in C. elegans. A genome-wide RNA interference (RNAi) screen resulted in the identification of two such novel NMD genes, which are essential for proper embryonic development, and as such represent a new class of essential NMD genes in C. elegans that we have termed smgl (for smg lethal). We show that the encoded proteins are conserved throughout evolution and are required for NMD in C. elegans and also in human cells.[Keywords: Nonsense-mediated decay; smg genes; RNAi screens; exon junction complex; C. elegans] Supplemental material is available at http://www.genesdev.org. Nonsense-mediated mRNA decay (NMD) is a highly conserved surveillance mechanism present in all eukaryotes examined that prevents the synthesis of truncated proteins. It does so by promoting the degradation of mRNAs containing premature translation termination codons (PTCs) (for a recent review, see Maquat 2004). The functional importance of NMD is highlighted by the fact that this pathway targets for degradation a wide array of endogenous transcripts, as well as erroneously processed transcripts and transcripts carrying spontaneous mutations (for review, see Rehwinkel et al. 2006). It is proposed that NMD modulates the phenotypic outcome of many diseases, since ∼30% of inherited genetic disorders are caused by frameshift or nonsense mutations that generate premature termination codons (PTCs). Therefore, effectors of NMD are potential targets for therapeutic intervention (Frischmeyer and Dietz 1999;Holbrook et al. 2004).Genetic screens in the nematode Caenorhabditis elegans identified seven genes that are required for the degradation of nonsense mutant mRNAs of the unc-54 myosin heavy chain gene (Hodgkin et al. 1989;Pulak and Anderson 1993;Cali et al. 1999). In addition to their suppression-of-unc phenotype, these mutations cause abnormal morphogenesis of the male bursa and the hermaphrodite vulva, and accordingly these genes were termed smg-1-7 (for suppressor with morphological effect on genitalia). In the yeast Sac...

show abstract

mentioning

confidence: 90%

Mechanistic insights and identification of two novel factors in the C. elegans NMD pathway

Longman¹,

Plasterk²,

Johnstone³

et al. 2007

Genes Dev.

149

187

View full text Add to dashboard Cite

show abstract

“…Some models and some experimental results indicate that mechanistic distinctions between premature and normal termination lead to preferential association of Upf1 with mRNPs undergoing premature termination (Amrani et al 2004(Amrani et al , 2006Bühler et al 2006;Johansson et al 2007;). Other models and other data suggest that Upf1 associates with all terminating ribosomes, and specificity for premature termination events is achieved by subsequent Upf1 interactions with factors that could only remain mRNA-associated if termination had occurred upstream of its normal site (Peltz et al 1993;Le Hir et al 2000;Sun and Maquat 2000).…”

Section: Introductionmentioning

confidence: 99%

Yeast Upf1 CH domain interacts with Rps26 of the 40S ribosomal subunit

Min

Roy

Amrani

et al. 2013

RNA

View full text Add to dashboard Cite

The central nonsense-mediated mRNA decay (NMD) regulator, Upf1, selectively targets nonsense-containing mRNAs for rapid degradation. In yeast, Upf1 preferentially associates with mRNAs that are NMD substrates, but the mechanism of its selective retention on these mRNAs has yet to be elucidated. Previously, we demonstrated that Upf1 associates with 40S ribosomal subunits. Here, we define more precisely the nature of this association using conventional and affinity-based purification of ribosomal subunits, and a two-hybrid screen to identify Upf1-interacting ribosomal proteins. Upf1 coimmunoprecipitates specifically with epitope-tagged 40S ribosomal subunits, and Upf1 association with high-salt washed or puromycin-released 40S subunits was found to occur without simultaneous eRF1, eRF3, Upf2, or Upf3 association. Two-hybrid analyses and in vitro binding assays identified a specific interaction between Upf1 and Rps26. Using mutations in domains of UPF1 known to be crucial for its function, we found that Upf1:40S association is modulated by ATP, and Upf1:Rps26 interaction is dependent on the N-terminal Upf1 CH domain. The specific association of Upf1 with the 40S subunit is consistent with the notion that this RNA helicase not only triggers rapid decay of nonsense-containing mRNAs, but may also have an important role in dissociation of the premature termination complex.

show abstract

“…Possible candidates for involvement in termination are poly(A) binding protein (PABP) and Upf proteins (Upf1, Upf2 and Upf3). Interaction of eRF3 with PABP links termination of translation with initiation (Hoshino et al, 1999), while interaction with Upf involves eRF proteins in nonsense-mediated decay (Amrani et al, 2006). The genetic data, derived mostly from S. cerevisiae, strongly suggest that the functions of eRF1 and eRF3 are not restricted to termination of translation (Inge-Vechtomov et al, 2003).…”

Section: Resultsmentioning

confidence: 91%

“…Shifts in the reading frame occur at a frequency near 3 x 10 -5 (Atkins et al, 1991) and may lead to the synthesis of non-functional products because shifts in the reading frame will often create a premature termination codon (PTC). Eukaryotic cells possess a mechanism known as nonsense-mediated mRNA decay (NMD) that recognizes and degrades mRNA molecules containing premature termination codons (Amrani et al, 2006) (Figure 4). NMD is mediated by the trans-acting factors Upf1, Upf2 and Upf3, all of which directly interact with eRF3; only Upf1 interacts with eRF1 (Czaplinski et al, 1998;Wang et al, 2001).…”

Section: Subneofunctionalization In a Family Of Termination Factors Gmentioning

confidence: 99%