(Cao and Parker 2003). Although the molecular mechanism that leads to distal stop codons leading to slower rates of decapping is not known, it does demonstrate that there are multiple steps in the targeting of an mRNA for NMD. Additional factors can also inﬂuence the process of NMD in yeast. Both Upf1 and Upf2 are phosphorylated (De Pinto et al. 2004; Wang et al. 2006), and phosphorylation of Upf2 may affect NMD (Wang et al. 2006). In addition, strains lacking the Ebs1 protein, which is homologous to the meta- zoan NMD factor Smg7 and contains a 14-3-3 domain for binding phosphoproteins, show partial defects in NMD (Luke et al. 2007). Interestingly, Ebs1 is also regulated by the NMD pathway, which might provide a feedback regula- tory loop for maintaining active NMD under some conditions (Ford et al. 2006). No-go decay: A second quality control system for mRNA translation, NGD, leads to endonucleolytic cleavage of mRNAs with strong stalls in translation elongation (Doma and Parker 2006; reviewed in detail in Harigaya et al. 2010). After such cleavage, the 39 mRNA fragment is degraded by Xrn1, and the 59 fragment is degraded primarily by the cy- toplasmic exosome (Doma and Parker 2006). No-go decay can occur at a wide range of translation elongation stalls, including strong stem loops, rare codons, polyLys or polyArg runs, sites of depurination, and possibly at frameshift sites (Doma and Parker 2006; Gandhi et al. 2008; Chen et al. 2010; Kuroha et al. 2010; Letzring et al. 2010; Belew et al. 2011). To date, no speciﬁc mRNAs that are predominantly degraded by NGD have been identiﬁed, and the suggestion is that NGD primarily functions to degrade aberrant or dam- aged mRNAs, which could be produced by chemicals or ultraviolet light exposure (Y. Harigaya and R. Parker, un- published data). The endonuclease(s) that cleaves the mRNA during NGD has not been identiﬁed. At some translation stalls, NGD is promoted by the Dom34 and Hbs1 proteins, which are paralogs of the trans- lation termination factors eRF1 and eRF3 (Doma and Parker 2006). Structural analyses indicate that Dom34 and Hbs1 fold and interact similarly to eRF1 and eRF3, respectively (Lee et al. 2007; Graille et al. 2008; Chen et al. 2010; Van Den Elzen et al. 2010). Moreover, Dom34 and Hbs1 bind the ribosome in the empty A site (Becker et al. 2011). This similarity to translation termination complexes suggested that Dom34 and Hbs1 function at elongation stalls to termi- nate translation, which has been demonstrated using recon- stituted systems from both yeast and mammals (Shoemaker et al. 2010; Pisareva et al. 2011). However, under some conditions, or at very strong translation pauses, Hbs1 and Dom34 are not required for NGD (Passos et al. 2009; Chen et al. 2010; Kuroha et al. 2010). On the basis of these observations, a working model for NGD can be proposed (Figure 4). During translation elon- gation, the ribosome can be paused for a variety of reasons. If the A site is empty during a prolonged elongation stall, it allows for a Dom34/Hbs1/GTP complex, rather than cog- nate aminoacyl-tRNA, to interact with the A site in the stalled ribosome, leading to dissociation of the peptide and tRNA or a peptide-tRNA conjugate, while maintaining the ribosome on the mRNA. At this stage, three events can occur. First, the mRNA can be cleaved at the vicinity of the “terminated” ribosome. Although the identity of the nucle- ase is unknown, it is likely to be physically associated with the stalled ribosome. Note that the mRNA cleavage could possibly occur before the release of the peptide-tRNA con- jugate. Second, the ribosomes can be released by an un- known mechanism, which may or may not be similar to ribosome recycling at a regular termination codon. Release of the ribosomes is predicted to limit cleavage of the mRNA by preventing the recruitment of the nuclease. Third, the released nascent peptide or peptide tRNA-conjugate would be subject to ubiquitin-proteasome-mediated degradation, possibly in conjunction with peptide-tRNA hydrolysis. Non-stop decay: Another mechanism of mRNA quality control is the rapid degradation of mRNAs that do not contain translation termination codons, which is referred to as non-stop decay (NSD) (Frischmeyer et al. 2002; Van Hoof et al. 2002) (Figure 5). Such mRNAs naturally occur due to use of polyadenylation sites within open reading frames, which are estimated to occur at 10% of the transcriptional events (Van Hoof et al. 2002). In addition, such non-stop mRNAs could also arise due to mutations, readthrough of stop codons due to PSI+ that limits the translation termina- tion factor function (Wilson et al. 2005), or endonuclease cleavage sites with the open reading frame. The process of NSD appears triggered by a ribosome reaching the 39 end of the mRNA and being unable to ter- minate translation. In this situation, the mRNA is rapidly degraded in a process that requires the exosome and the Ski7, Ski2, Ski3, and Ski8 proteins. NSD is distinguished from 39 to 59 decay of mRNAs by requiring the GTPase domain of Ski7, which is similar to Ef1a and is thought to interact with the ribosome (Van Hoof et al. 2002). NSD is also mechanistically different from normal 39 to 59 decay of mRNAs in that it can utilize either endonuclease or exonu- clease activity of Rrp44, whereas 39 to 59 decay of normal mRNAs appears to require the exonuclease activity of Rrp44 (Schaeffer and Van Hoof 2011). Given this, the prevailing model of NSD is that a stalled ribosome at the 39 end of the mRNA is recognized by the Ski7 protein, which then recruits the Ski2/Ski3/Ski8 complex and the exosome to degrade the mRNA in a 39 to 59 direction. In the absence of Ski7 or the exosome, nonstop mRNAs are subject to accelerated decapping and 59 to 39 degradation (Inada and Aiba 2005), perhaps because of the failure to recycle terminating ribo- somes for continued efﬁcient translation initiation. An unre- solved issue is how the ribosome is removed from the mRNA and if Ski7 hydrolyzes GTP to promote its dissociation. The peptides produced by non-stop mRNAs are also subject to rapid degradation in a proteasome-mediated manner. In this case, two different ubiquitin ligases have RNA Decay in Yeast 685