Regulation by signal transduction paths: Multiple signal transduction pathways impinge on mRNA decapping. First, Ste20 has been observed to phosphorylate Dcp2 and affect its assembly into P-bodies. Ste20 phosphorylation of Dcp2 also affects the degradation of certain mRNAs (Yoon et al. 2010). Second, Pat1 is a target of PKA, and phosphoryla- tion of Pat1 limits its ability to assemble into P-bodies (Ramachandran et al. 2011), although how this affects speciﬁc protein interactions or mRNA decay is not clear. Third, when the growth regulatory Tor kinase is inhibited, the activation of the Rim15 kinase leads to phosphorylation of the paralogous Igo1 and Igo2 proteins, which then in- teract with Dhh1 and stabilize mRNAs required for entry into G0 (Talarek et al. 2010). One anticipates that other signal transduction pathways will regulate the mRNA turn- over machinery. On the basis of genome-wide studies Dhh1, Edc1, Edc3, Pop2, Ccr4, Xrn1, Dcp2, and Dcp1 are also known to be phosphoproteins and could be targets of such signal transduction pathways. 39 to 59 mRNA degradation The second pathway of mRNA decay following deadenyla- tion is 39 to 59 degradation, which is catalyzed by the exo- some and various cofactors (Table 3) (Anderson and Parker 1998). The exosome is a multiprotein complex consisting of 10 main proteins, including six members of the RNase PH protein family and three small RNA-binding proteins (Allmang et al. 1999), which together form a ring structure analogous to bacterial PNPase (Liu et al. 2006), and the Rrp44/Dis3 protein, which has both an exonuclease and endonuclease domain (Lebreton et al. 2008; Schaeffer et al. 2009). In addition to its roles in the cytoplasm, the exosome is involved in numerous nuclear RNA processing and degradation processes (see below and reviewed in Lykke-Andersen et al. 2009). In the nucleus, the exosome is also associated with Rrp6, another 39 to 59 exonuclease, Rrp47, and Mpp6 (Mitchell et al. 2003; Milligan et al. 2008; Synowsky et al. 2009), which have roles in nuclear function of the exosome (see below). Despite the similarity of the core ring domain to active exonucleases, the only active nuclease sites in the exosome appear to be present in the Rrp44/Dis3 protein (Liu et al. 2006; Dziembowski et al. 2007). The exosome is then thought to function by the core ring structure serving as a binding platform for proteins targeting the exosome to various substrates and to channel the RNA to the active sites of Rrp44/Dis3 (Bonneau et al. 2009). For the degradation of cytoplasmic mRNA, the exosome requires the Ski proteins (Anderson and Parker 1998; Van Hoof et al. 2000b; Araki et al. 2001). The Ski7 protein appears stably bound to the cytoplasmic exosome through the Ski4 subunit (Van Hoof et al. 2002). The Ski2, Ski3, and Ski8 proteins form a separate protein complex (Brown et al. 2000; Wang et al. 2005). The Ski2/3/8 complex interacts with Ski7 (Araki et al. 2001; Wang et al. 2005), and this 682 R. Parker interaction, which appears to occur between Ski7 and the Ski3 and Ski8 proteins, is required for 39 to 59 degradation of mRNAs. The Ski2 protein is an ATPase of the RNA heli- case family and presumably utilizes the energy of ATP hy- drolysis to unwind substrates and/or dissociate bound proteins to deliver the RNA to the exosome. Interestingly, RNA processing and degradation by the nuclear exosome require the related ATPase Mtr4, suggesting that this is a general feature of exosome function (reviewed in Lykke- Andersen et al. 2009). There are several unresolved issues with regards to 39 to 59 degradation of mRNAs. For example, the role of the Ski complex is not well understood. Moreover, although mRNAs can have differences in their rates of 39 to 59 degradation (Cao and Parker 2001), the features of mRNAs that dictate different rates of 39 to 59 degradation are not understood. In mammalian cells, sequence-speciﬁc RNA-binding proteins can recruit the exosome directly to mRNAs, and similar events might exist in yeast cells (e.g., Chen et al. 2001). Finally, whether some mRNAs are normally degraded by the exosome or whether 39 to 59 degradation is the major pathway of cytoplasmic mRNA under some growth condi- tions is not resolved. Other mRNA decay pathways Some observations imply that there will be two additional mechanisms by which yeast mRNAs are degraded. First, the vacuolar nuclease Rny1 can degrade tRNAs, rRNAs, and even small nuclear RNA (snRNAs) (Thompson and Parker 2009; N. Luhtala and R. Parker, unpublished observations). Given this, one anticipates some mRNAs will also be de- graded by Rny1 either during the process of autophagy or speciﬁc targeting of some mRNAs to the vacuole or because Rny1 can enter the cytosol and degrade mRNAs under some conditions (Thompson and Parker 2009). A second nuclease that probably targets mRNAs during stress is Nuc1. Nuc1 is a general nuclease that is localized to the mitochondria, but during stress or in high cell densities is released to the cy- tosol through the mitochondrial porins and then is trans- ported to the nucleus where it can play a role in apoptosis (Buttner et al. 2007). Interestingly, Nuc1 is also known to target the mRNAs produced by the double-stranded RNA killer virus, suggesting that it could also target some, or all, cytoplasmic mRNAs under these conditions (Liu and Die- ckmann 1989). A potential role of Nuc1 in mRNA decay is suggested by its negative genetic interactions with Ski2, -3, -7, -8, and Xrn1 (Costanzo et al. 2010). mRNA Quality Control Pathways Cytoplasmic quality control Several cytoplasmic quality control mechanisms degrade eukaryotic mRNAs that are defective in translation (Doma and Parker 2007). An emerging principle is that aberrant