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• W2009504671 abstract "Recent work from Lemay et al., 2010Lemay J.-F. D'Amours A. Lemieux C. Lackner D.H. St-Sauveur V.G. Bähler J. Bachand F. Mol. Cell. 2010; 37 (this issue): 34-45Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar in this issue of Molecular Cell reveals a role for a nuclear poly(A)-binding protein in promoting degradation of small nucleolar RNAs (snoRNAs) by the nuclear exosome. Recent work from Lemay et al., 2010Lemay J.-F. D'Amours A. Lemieux C. Lackner D.H. St-Sauveur V.G. Bähler J. Bachand F. Mol. Cell. 2010; 37 (this issue): 34-45Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar in this issue of Molecular Cell reveals a role for a nuclear poly(A)-binding protein in promoting degradation of small nucleolar RNAs (snoRNAs) by the nuclear exosome. When the RNA polymerase reaches the end of mRNA coding genes, the nascent transcript is cleaved and a poly(A) tail is appended to the 3′ end of the molecule. A large complex of proteins, the cleavage and polyadenylation machinery, is responsible for the recognition of 3′-processing signals and for cleavage, and an associated poly(A) polymerase (Pap1p) synthesizes the terminal polyadenylate (Buratowski, 2005Buratowski S. Curr. Opin. Cell Biol. 2005; 17: 257-261Crossref PubMed Scopus (147) Google Scholar, Zhao et al., 1999Zhao J. Hyman L. Moore C. Microbiol. Mol. Biol. Rev. 1999; 63: 405-445Crossref PubMed Google Scholar). The presence of a 3′ poly(A) tail is both a signal that the mRNA synthesis is complete and a functional element that will promote export from the nucleus and translation. Its position close to the end of the coding region of the mRNA is also a hallmark of quality, preventing degradation by the quality control system that detects the occurrence of premature stop codons. The size of the poly(A) tail (70–100 nt in Saccharomyces cerevisiae) is also crucial, as its shortening in the cytoplasm is the first event committing the transcript to degradation. Poly(A)-binding proteins are required for a readout of the tail functions and to influence its synthesis and length by affecting the processivity of the poly(A) polymerase (Mangus et al., 2003Mangus D.A. Evans M.C. Jacobson A. Genome Biol. 2003; 4: 223Crossref PubMed Scopus (450) Google Scholar). In S. cerevisiae, two proteins (Pab1p and Nab2p) that recognize the poly(A) tail have been described and extensively studied. Although both proteins shuttle between the nucleus and the cytoplasm, their main subcellular localization is cytoplasmic (Pab1p) and nuclear (Nab2p). While a cytoplasmic role for Pab1p in translation is clearly established, the nuclear role of the two proteins is still a matter of controversy, and it is not clear which one is directly involved in the regulation of poly(A) tail synthesis and its nuclear function(s) (Dunn et al., 2005Dunn E.F. Hammell C.M. Hodge C.A. Cole C.N. Genes Dev. 2005; 19: 90-103Crossref PubMed Scopus (92) Google Scholar, Hector et al., 2002Hector R.E. Nykamp K.R. Dheur S. Anderson J.T. Non P.J. Urbinati C.R. Wilson S.M. Minvielle-Sebastia L. Swanson M.S. EMBO J. 2002; 21: 1800-1810Crossref PubMed Scopus (140) Google Scholar). Poly(A) tailing is not only instrumental to express the message carried by an RNA, but also to promote maturation or degradation. A different polyadenylation pathway, dependent on an alternative poly(A) polymerase (Trf4p or Trf5p in S. cerevisiae), exists (Houseley and Tollervey, 2008Houseley J. Tollervey D. Biochim. Biophys. Acta. 2008; 1779: 239-246Crossref PubMed Scopus (68) Google Scholar). This pathway tags a different class of substrates for faster (or more efficient) degradation by the nuclear exosome, a protein complex endowed with both exo- and endonuclease activity (Lebreton and Seraphin, 2008Lebreton A. Seraphin B. Biochim. Biophys. Acta. 2008; 1779: 558-565Crossref PubMed Scopus (62) Google Scholar). In many cases, degradation is halted by stable ribonucleoprotein complexes, and exonuclease trimming results in the production of mature and stable RNAs, as in the case of the small nucleolar RNAs (snoRNAs). It is unclear whether degradative polyadenylation is coupled to the termination of transcription and/or to 3′ end processing of the primary transcript or if it occurs posttranscriptionally on substrates that cannot be degraded efficiently by the exosome, for instance due to secondary structures. Importantly, it is also unclear whether the unstructured poly(A) tail is required in vivo to promote more efficient degradation or whether it somehow serves for addressing the exosome to the substrate. Thus, the poly(A) tail can promote very different fates, which raises the important question of what differs in the readout of the same signal. One possibility is that binding of a poly(A)-binding protein (e.g., Pab1p) after cleavage and polyadenylation “marks” the poly(A) tails that have a cytoplasmic fate while masking at the same time a dangerous degradation signal. A poly(A) tail that would not associate with poly(A)-binding proteins during or shortly after synthesis (as could be the case of a tail added posttranscriptionally by Trf4p) would be exposed to the degradative activity of the exosome. The paper from Bachand and colleagues in this issue of Molecular Cell (Lemay et al., 2010Lemay J.-F. D'Amours A. Lemieux C. Lackner D.H. St-Sauveur V.G. Bähler J. Bachand F. Mol. Cell. 2010; 37 (this issue): 34-45Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar) challenges to some extent this view and provides a unique perspective on the function of poly(A)-binding proteins. The authors show that deletion of the gene encoding a nuclear poly(A)-binding protein in Schizosaccharomyces pombe, Pab2, leads to stabilization of extended forms of several snoRNAs. Importantly, these precursors to the mature snoRNAs are polyadenylated by a poly(A) polymerase that turns out to be distinct from the S. pombe homolog of Trf4p. The same extended forms are stabilized by deletion of Rrp6p (a nuclear exonuclease that is associated with the exosome), but in a double mutant rrp6Δ pab2Δ a further stabilization of the precursors was not observed, suggesting that Rrp6p and Pab2p work in the same pathway. Importantly, Pab2p binds these polyadenylated forms in vivo and interacts directly with Rrp6p, both in vivo and in vitro. This suggests that the binding of Pab2 to the poly(A) tail is required to target these extended transcripts to degradation via the direct interaction between Pab2p and the exosome (Figure 1). These findings have two important implications: first, they provide evidence that the presence of the poly(A) tail can recruit the exosome (as opposed to favoring its catalytic activity); second, the mere (and presumably early) binding of a poly(A)-binding protein is not sufficient to prevent degradation but actually, in some conditions, promotes it. The authors suggest that this might reveal the existence of an alternative pathway to generate a mature form of snoRNAs: either transcription ends at a proximal site (presumably via the action of a homolog of the S. cerevisiae Nrd1 complex, involved in termination of independently transcribed snoRNA genes) or it ends at a downstream site where the nascent transcript is processed by the cleavage and polyadenylation machinery and where it interacts with Pab2b. The presence of Pab2 would lead to the recruitment of the exosome and subsequent trimming of these transcripts to their mature length. However, there is more to the story. In another recent article (Lemieux and Bachand, 2009Lemieux C. Bachand F. Nucleic Acids Res. 2009; 37: 3418-3430Crossref PubMed Scopus (27) Google Scholar), the same group shows that Pab2p also binds cotranscriptionally to mRNAs and that this occurs even before the poly(A) tail synthesis (Figure 1B). In spite of this, no stabilization of the tested mRNAs nor an effect on the length of the poly(A) tail was observed in pab2Δ cells (Lemay et al., 2010Lemay J.-F. D'Amours A. Lemieux C. Lackner D.H. St-Sauveur V.G. Bähler J. Bachand F. Mol. Cell. 2010; 37 (this issue): 34-45Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar), suggesting that the presence of Pab2p on the poly(A) tail does not target these transcripts to the nuclear degradation machinery. Rather, Pab2p is found in polysomes, indicating that it remains associated with the mRNA during translation. Therefore, what determines whether RNAs that share the same tail, possibly generated by the same apparatus and with the same protein bound to it, are targeted to the exosome for degradation or to the cytoplasm for translation remains a hot question. It is obviously possible that other proteins, aside from Pab2p, bind differentially to mRNAs and snoRNAs, but it remains unexplained how these species are distinguished in the act of transcription if they are processed by the same 3′ end apparatus. One possibility is that their fate is determined kinetically via a “take the money and run” strategy. If the RNA is not exported fast enough from the nucleus, it is targeted to a default exosome pathway for degradation or processing. If so, the presence of Pab2p on the poly(A) tail might not have a function in the nucleus other than that of a trigger that would determine the threshold above which the nuclear residency time is not compatible with the life of an mRNA. The Nuclear Poly(A)-Binding Protein Interacts with the Exosome to Promote Synthesis of Noncoding Small Nucleolar RNAsLemay et al.Molecular CellJanuary 15, 2010In BriefPoly(A)-binding proteins (PABPs) are important to eukaryotic gene expression. In the nucleus, the PABP PABPN1 is thought to function in polyadenylation of pre-mRNAs. Deletion of fission yeast pab2, the homolog of mammalian PABPN1, results in transcripts with markedly longer poly(A) tails, but the nature of the hyperadenylated transcripts and the mechanism that leads to RNA hyperadenylation remain unclear. Here we report that Pab2 functions in the synthesis of noncoding RNAs, contrary to the notion that PABPs function exclusively on protein-coding mRNAs. Full-Text PDF Open Archive" @default.
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• W2009504671 title "Nuclear Poly(A)-Binding Proteins and Nuclear Degradation: Take the mRNA and Run?" @default.
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