CONTENTS, continued Nonsense-mediated decay: No-go decay: Non-stop decay: Quality control of nuclear mRNA processing Quality control of pre-mRNA splicing: Quality control of 39 end generation: Intergenic, Intragenic, Promoter-Associated, and Antisense RNAs Decay of tRNA, rRNAs, snRNAs, and snoRNAs tRNAs rRNA decay snRNAs/snoRNAs Degradation of RNAs in Mitochondria Future Perspectives Aover, which plays several roles in yeast cells. First, the LL RNA species in eukaryotic cells are subject to turn- differential degradation of messenger RNA (mRNAs) can play an important role in setting the basal level of mRNA expression and how that mRNA level is modulated by environmental stimuli. Second, numerous quality control systems degrade aberrant transfer RNA (tRNAs) and ribo- somal RNA (rRNAs), as well as aberrant mRNAs, which might otherwise encode a defective protein product. Third, RNA degradation removes the by-products of gene expres- sion, including excised introns and other RNA pieces re- leased during RNA processing. Finally, RNA degradation mechanisms functions in removing intergenic, intragenic, promoter-associated, and antisense RNAs that arise either as regulatory RNAs or transcriptional noise. Here I review our understanding of the pathways and nucleases of RNA turnover by considering the different clas- ses of RNAs and how they are degraded. Three common themes emerge from this review. First, most RNA degrada- tion mechanisms funnel RNAs to the cytoplasmic Xrn1 or nuclear Rat1 59 to 39 nucleases, or to the exosome, which is a conserved cytoplasmic and nuclear complex with both 39 to 59 exonuclease activities and an endonuclease cleavage site. Second, where examined, all RNAs are subject to qual- ity control systems where nonfunctional RNAs are more rap- idly degraded. Third, the RNA pathways are modulated by environmental inputs and interact with other cellular pro- cesses including translation, RNA processing, transcription, and stress responses. Degradation of mRNA Cytoplasmic turnover of mRNA Cytoplasmic degradation of yeast mRNAs occurs by two general pathways, both of which are initiated by shortening 672 R. Parker 683 685 685 686 687 688 689 690 690 691 691 692 692 of the 39 poly(A) tail in a process referred to as deadenyla- tion (Muhlrad and Parker 1992; Decker and Parker1993) (Figure 1A). Deadenylation in yeast is carried out by the Pan2/Pan3 complex as well as the by Ccr4/Pop2/Not com- plex (Brown and Sachs 1998; Tucker et al. 2001). Following deadenylation, mRNAs can be subjected to 39 to 59 degra- dation by the exosome (Anderson and Parker 1998). More commonly, mRNAs are decapped by the Dcp1/Dcp2 decapp- ing enzyme and then subjected to 59 to 39 degradation by Xrn1 (Hsu and Stevens 1993; Muhlrad et al. 1994, 1995; Dunckley and Parker 1999; Van Dijk et al. 2002; Steiger et al. 2003). Yeast also contain specialized mRNA decay pathways that act in response to aberrancies in translation (Figure 1B). In these cases, mRNAs can be subject to either deadenylation independent decapping (Muhlrad and Parker 1994), rapid 39 to 59 degradation (Van Hoof et al. 2002), or endonuclease cleavage (Doma and Parker 2006). The available evidence suggests that these specialized mechanisms function primar- ily on aberrant mRNAs, although the nonsense-mediated decay (NMD) pathway does degrade a pool of “normal” mRNAs (see section on mRNA Quality Control Pathways). Several observations suggest that, at least during mid-log growth phase, decapping is the predominant pathway of mRNA degradation. First, strains lacking the decapping enzyme grow very slowly or are lethal in some strain backgrounds (Beelman et al. 1996; Dunckley and Parker 1999; Giaever et al. 2002), while strains defective in cyto- plasmic 39 to 59 mRNA degradation grow relatively normally (Anderson and Parker 1998; Giaever et al. 2002). Second, strains defective in decapping or 59 to 39 degradation show changes in both the steady-state levels and decay rates of many mRNAs (Beelman et al. 1996; He et al. 2003; Van Dijk et al. 2011). Finally, the genome-wide mapping of endonu- clease sites in mRNAs has revealed that few yeast mRNAs are subject to endonucleolytic degradation (Y. Harigaya and