residues of the A tail, but the 39 most region is exposed and thereby rapidly deadenylated by Pan2. Since pan2Δ strains show relatively normal deadenylation of reporter mRNAs (Tucker et al. 2001), Ccr4 then appears to be responsible for the continued deadenylation of the mRNA. Since the Ccr4 complex is inhibited by Pab1 (Tucker et al. 2002), this phase of deadenylation implies that Pab1 is at least partially dissociating from the poly(A) tail. However, in strains lack- ing Ccr4 activity, the Pan2 complex can continue to dead- enylate mRNAs, although at a slower rate than Ccr4 (Tucker et al. 2001). Interestingly, the Pan2 complex stalls at an A tail of 20–25 residues (Daugeron et al. 2001; Tucker et al. 2001), which might be a length at which the Pab1 can no longer associate with the mRNA, and therefore Pan2 activity becomes limited (Tucker et al. 2001). Interestingly, once the poly(A) tail reaches an oligo(A) length of 10–12 residues, the mRNA can become a substrate for decapping and for binding of the Pat1/Lsm1–7 complex at the 39 end (Tharun and Parker 2001; Chowdhury et al. 2007), which enhances the rate of decapping. This exchange of the Pab1 protein for the Pat1/Lsm1–7 complex is part of the mechanism that allows decapping to be promoted following deadenylation (see below). Control of deadenylation: Three types of interactions are known to modulate deadenylation rate, either generally or on speciﬁc mRNAs. First, because the Ccr4 and Pan2 dead- enylases are inﬂuenced by the binding of Pab1 to the poly (A) tail, the rate of deadenylation is inﬂuenced by features of the Pab1–poly(A) interaction and its dynamics. Because Pab1–mRNA interactions are inﬂuenced by translation per se, this leads to deadenylation being coupled to aspects of translation. Second, key regulators of deadenylation on spe- ciﬁc mRNAs are sequence-speciﬁc binding proteins that ei- ther directly, or indirectly, recruit the deadenylases to the mRNA to accelerate deadenylation. Finally, deadenylation is regulated in response to environmental cues, including stress and nutrient limitations. On the basis of the biochemical analyses of deadenylases, a working model for understanding how deadenylation is affected by mRNP dynamics is that when Pab1 is present on the poly(A) tail, the Ccr4 deadenylase is inhibited and Pan2 is stimulated, whereas, when Pab1 dissociates, Ccr4 dead- enylation is accelerated and Pan2 deadenylation is inhibited. Consistent with this view, self-association of Pab1 limits its binding to poly(A) and increases Ccr4-dependent deadenyla- tion (Simon and Seraphin 2007; Yao et al. 2007). Moreover, strains defective in Pab1 show a defect in the initial rapid Pan2-dependent poly(A) shortening (Caponigro and Parker 1995; Morrissey et al. 1999; Simon and Seraphin 2007). This model suggests that some of the effects of trans- lation on deadenylation can be understood by their effects on Pab1 binding the poly(A) tail. For example, defects in translation initiation caused by a poor AUG context, a stem loop in the 59 UTR, or mutations in translation initiation factors can increase the rates of deadenylation of yeast mRNAs (Muhlrad et al. 1995; Lagrandeur and Parker 1999; Schwartz and Parker 1999). One possibility is that defects in translation initiation either directly or indirectly destabilize Pab1 binding the poly(A) tail. Note that this model also predicts that Pan2-mediated deadenylation would be compromised by decreases in translation initiation. Sur- prisingly, in temperature-sensitive eIF4E strains, deadenyla- tion of the Gal1 mRNA increases even in a ccr4Δ strain, which has been interpreted to suggest that eIF4E can also inhibit Pan2-based deadenylation (Lee et al. 2010). However, another possibility is that the “deadenylation” seen in a cdc33-1 ccr4Δ strain is not due to Pan2, but may be due to the cytoplasmic exosome (or to an unknown additional dead- enylases), which is suggested by the observation that dead- enylation is restored in a ccr4Δ pan2Δ strain when pab1 is mutated (M. Tucker and R. Parker, unpublished observation). Deadenylation is also affected by aspects of translation termination. For example, premature translation termina- tion accelerates poly(A) shortening as part of the process of NMD (see below and Cao and Parker 2003; Mitchell et al. 2003). This accelerated deadenylation may be a conse- quence of NMD leading to repression of translation and/or to dissociation of Pab1 from the mRNA, since decapping tri- ggered by NMD is independent of the poly(A) tail (Muhlrad and Parker 1994). Similarly, the Tpa1 protein, a proline hy- droxylase that binds poly(A) and interacts with translation termination factors, can inﬂuence the rate of deadenylation (Keeling et al. 2006; Henri et al. 2010). The coupling of translation termination to deadenylation has been suggested to occur through direct interactions of the translation termination factor eRF3 with Pab1 (Cosson et al. 2002). This interaction appears to inﬂuence mRNA deadenylation since overexpression or deletion of the N-terminal domain of eRF3, where Pab1 interacts, leads to defects in deadenylation and mRNA decay (Kobayashi et al. 2004; Funakoshi et al. 2007). Since this effect seems to be primarily on the Ccr4 deadenylase (Funakoshi et al. 2007), one possibility is that eRF3–Pab1 interactions during trans- lation termination transiently dissociate Pab1 from the poly (A) tail and increase deadenylation. However, it is important to note that translation termination is not required for dead- enylation since mRNAs that never initiate translation due to stem-loop structures in their 59 UTRs still deadenylate rap- idly (Beelman and Parker 1994; Muhlrad et al. 1995). Deadenylation also appears to be coupled to the process of transcription. The Rpb4 and Rpb7 subunits of RNA poly- merase II are required for optimal deadenylation rates of yeast mRNAs (Lotan et al. 2005, 2007), and this has been proposed to occur by Rpb4 and Rbp7 loading on the mRNA during transcription to regulate cytoplasmic function (see Future Perspectives). Control of deadenylation by mRNA-speciﬁc features: There are now several examples of speciﬁc proteins that bind mRNAs in a sequence-speciﬁc manner to control dead- enylation. Moreover, in many other cases, 39 UTR elements RNA Decay in Yeast 675