Table 3 Exosome and associated proteins involved in 39 to 59 degradation of RNAs Component Core exosome Cytoplasmic cofactors Ski7 Ski2/Ski3/Ski8 complex Nuclear cofactors Rrp6 Rrp47 (Lrp1) Mpp6 Tramp complexes (Trf4 or Trf5) Features Six RNasePH domain proteins (no active sites) Rrp41, Rrp42, Rrp43, Rrp45, Rrp46, Mtr3 3 RNA-binding subunits (Rrp4, Rrp40, Csl4) One catalytic subunit, Rrp44, with both endo and exo active sites Functions in both RNA processing and degradation in cytoplasm and nucleus Binds Csl4 subunit of core Required for 39 to 59 decay of mRNAs GTPase domain required for non-stop decay Interacts with Ski2/Ski3/Ski8 complex Required for 39 to 59 mRNA decay Ski2 is member of ATPase RNA helicase family Ski8 is WD40 protein Ski3 may function as scaffold 39 to 59 exonuclease of RNAseD family Associated with nuclear exosome Required for RNA processing and decay of RNAs in the nucleus Functions in retention of aberrant mRNAs at sites of transcription RNA-binding protein Required for RNA processing and nuclear RNA decay Associated with nuclear exosome RNA-binding protein Associated with nuclear exosome Required for RNA processing and nuclear RNA decay Consist of Mtr4 with 1 noncanonical poly(A) polymerase (Trf4 or Trf5) and 1 RNA-binding protein (Air1 or Air2) Required for several RNA-processing and nuclear RNA decay pathways Can promote processing/degradation in poly(A)-dependent and -independent manners by recruiting exosome to substrates Reference Lykke-Andersen et al. (2011) Van Hoof et al. (2000b, 2002); Wang et al. (2005) Anderson and Parker (1998); Brown et al. (2000); Araki et al. (2001); Wang et al. (2005) Butler and Mitchell (2011) Butler and Mitchell (2011) Milligan et al. (2008) Houseley and Tollervey (2006); San Paolo et al. (2009); Butler and Mitchell (2011) mRNAs are distinguished from the normal mRNAs by adap- tor proteins that interact with the translation machinery and direct the aberrant mRNA into a degradation pathway. Key issues for each quality control pathway are the biological role, the speciﬁcity of distinguishing normal from aberrant mRNAs, and the mechanism by which mRNAs are recog- nized and degraded. Nonsense-mediated decay: NMD is an mRNA quality control system that degrades mRNAs with aberrant trans- lation termination. NMD was ﬁrst described as a system that degrades mutant mRNAs with premature translation termination codons (Losson and Lacroute 1979). However, NMD degrades a wide variety of mRNAs that have aberrant translation termination events. Such substrates include mRNAs with long 39 UTRs that alter the relationship of the poly(A) tail to the stop codon (Muhlrad and Parker 1999a; Kebaara and Atkin 2009; Deliz-Aguirre et al. 2011), mRNAs with alternative translation initiation sites that that are out of frame with the main ORF and lead to premature termination (Welch and Jacobson 1999), mRNAs with upstream ORFs (Gaba et al. 2005; Guan et al. 2006), pre-mRNAs that contain introns with stop codons (He et al. 1993; Sayani et al. 2008), and mRNAs with frameshifts, where a proportion of the ribosomes are shifted into alterna- tive reading frames containing premature termination codons (Belew et al. 2011). In addition, one anticipates that errors in transcription or mis-splicing that introduce premature stop codons will generate substrates for NMD at a low level across many different genes. Consistent with this wide range of substrates, several genomic analyses have revealed that NMD targets a wide range of different mRNAs. As such, NMD is not just a quality control system but is also utilized by cells to degrade a subset of “normal” mRNAs, particularly those involved in cell-surface dynamics and chromosome structure (Lelivelt and Culbertson 1999; He et al. 2003; Guan et al. 2006). For many of these mRNAs it is not clear why they are substrates of NMD. One possibility is that they are lacking features that specify proper translation termination and as such are targeted by NMD (see below). Substrates for NMD are identiﬁed by the action of the interacting Upf1, Upf2, and Upf3 proteins (reviewed in Baker and Parker 2004). The recognition of an mRNA by the NMD pathway has several effects on the metabolism of the mRNA. Speciﬁcally, the mRNA is targeted for enhanced deadenylation (Muhlrad and Parker 1994; Cao and Parker 2003; Mitchell and Tollervey 2003), rapid deadenylation- RNA Decay in Yeast 683