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• W2895598897 abstract "Transcript buffering involves reciprocal adjustments between overall rates in mRNA synthesis and degradation to maintain similar cellular concentrations of mRNAs. This phenomenon was first discovered in yeast and encompasses coordination between the nuclear and cytoplasmic compartments. Transcript buffering was revealed by novel methods for pulse labeling of RNA to determine in vivo synthesis and degradation rates. In this Perspective, we discuss the current knowledge of transcript buffering. Emphasis is placed on the future challenges to determine the nature and directionality of the buffering signals, the generality of transcript buffering beyond yeast, and the molecular mechanisms responsible for this balancing. Transcript buffering involves reciprocal adjustments between overall rates in mRNA synthesis and degradation to maintain similar cellular concentrations of mRNAs. This phenomenon was first discovered in yeast and encompasses coordination between the nuclear and cytoplasmic compartments. Transcript buffering was revealed by novel methods for pulse labeling of RNA to determine in vivo synthesis and degradation rates. In this Perspective, we discuss the current knowledge of transcript buffering. Emphasis is placed on the future challenges to determine the nature and directionality of the buffering signals, the generality of transcript buffering beyond yeast, and the molecular mechanisms responsible for this balancing. Eukaryotic gene expression is a highly regulated process that is controlled at different levels and localized in distinct subcellular compartments. Protein-encoding genes are transcribed by nuclear RNA polymerase II (Pol II) into pre-mRNAs, which are processed by 5′ end capping, internal splicing, and poly-adenylation at their 3′ ends. The coupling of these distinct biochemical processes in the nucleus is coordinated by the C-terminal domain (CTD) of the largest subunit of Pol II and differential phosphorylation of the CTD during the transcription cycle of initiation, elongation, and release (Heidemann et al., 2013Heidemann M. Hintermair C. Voß K. Eick D. Dynamic phosphorylation patterns of RNA polymerase II CTD during transcription.Biochim. Biophys. Acta. 2013; 1829: 55-62Crossref PubMed Scopus (182) Google Scholar, Saldi et al., 2016Saldi T. Cortazar M.A. Sheridan R.M. Bentley D.L. Coupling of RNA polymerase II transcription elongation with pre-mRNA splicing.J. Mol. Biol. 2016; 428: 2623-2635Crossref PubMed Scopus (152) Google Scholar). Processed mRNAs are packaged co-transcriptionally into mRNA particles for export to the cytoplasm and subsequent translation by ribosomes. The elaborate process of producing a single mRNA molecule is a wise cellular investment, as an individual mRNA yields on average ∼1,000 protein molecules in yeast and 3,000–10,000 in mammalian cells (Milo and Phillips, 2016Milo R. Phillips R. Cell Biology by the Numbers. Garland Science, 2016Google Scholar). Translation is coupled to the default mRNA turn-over pathway involving removal of the 5′ cap and shortening of its poly(A) tail (Łabno et al., 2016Łabno A. Tomecki R. Dziembowski A. Cytoplasmic RNA decay pathways - enzymes and mechanisms.Biochim. Biophys. Acta. 2016; 1863: 3125-3147Crossref PubMed Scopus (110) Google Scholar). Degradation of individual mRNAs can also be induced by the absence of stop codons (non-stop translation decay [NSD]), the presence of aberrant stop codons (non-sense mediated decay [NMD]), specific RNA-binding proteins (RBPs), or microRNA binding. These processes involve mutational mistakes in the coding sequence of the mRNA or short recognition sequences and/or structural features in its UTRs. Several excellent reviews cover NSD, NMD, and targeted mRNA decay (Das et al., 2017Das S. Sarkar D. Das B. The interplay between transcription and mRNA degradation in Saccharomyces cerevisiae.Microb. Cell. 2017; 4: 212-228Crossref PubMed Scopus (15) Google Scholar, Godwin et al., 2013Godwin A.R. Kojima S. Green C.B. Wilusz J. Kiss your tail goodbye: the role of PARN, Nocturnin, and Angel deadenylases in mRNA biology.Biochim. Biophys. Acta. 2013; 1829: 571-579Crossref PubMed Scopus (36) Google Scholar, Łabno et al., 2016Łabno A. Tomecki R. Dziembowski A. Cytoplasmic RNA decay pathways - enzymes and mechanisms.Biochim. Biophys. Acta. 2016; 1863: 3125-3147Crossref PubMed Scopus (110) Google Scholar). The default mRNA degradation pathway, however, is the most relevant for the discussion of transcript buffering. The phenomenon of transcript buffering was revealed by recent studies carried out in the yeast Saccharomyces cerevisiae, which indicated that gene transcription frequencies in the nucleus are connected to the stability of their corresponding mRNAs in the cytoplasm (Baptista et al., 2017Baptista T. Grünberg S. Minoungou N. Koster M.J.E. Timmers H.T.M. Hahn S. Devys D. Tora L. SAGA is a general cofactor for RNA polymerase II transcription.Mol. Cell. 2017; 68: 130-143.e5Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, Haimovich et al., 2013aHaimovich G. Choder M. Singer R.H. Trcek T. The fate of the messenger is pre-determined: a new model for regulation of gene expression.Biochim. Biophys. Acta. 2013; 1829: 643-653Crossref PubMed Scopus (74) Google Scholar, Rodríguez-Molina et al., 2016Rodríguez-Molina J.B. Tseng S.C. Simonett S.P. Taunton J. Ansari A.Z. Engineered covalent inactivation of TFIIH-kinase reveals an elongation checkpoint and results in widespread mRNA stabilization.Mol. Cell. 2016; 63: 433-444Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, Shalem et al., 2011Shalem O. Groisman B. Choder M. Dahan O. Pilpel Y. Transcriptome kinetics is governed by a genome-wide coupling of mRNA production and degradation: a role for RNA Pol II.PLoS Genet. 2011; 7: e1002273Crossref PubMed Scopus (67) Google Scholar, Sun et al., 2012Sun M. Schwalb B. Schulz D. Pirkl N. Etzold S. Larivière L. Maier K.C. Seizl M. Tresch A. Cramer P. Comparative dynamic transcriptome analysis (cDTA) reveals mutual feedback between mRNA synthesis and degradation.Genome Res. 2012; 22: 1350-1359Crossref PubMed Scopus (179) Google Scholar, Sun et al., 2013Sun M. Schwalb B. Pirkl N. Maier K.C. Schenk A. Failmezger H. Tresch A. Cramer P. Global analysis of eukaryotic mRNA degradation reveals Xrn1-dependent buffering of transcript levels.Mol. Cell. 2013; 52: 52-62Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, Warfield et al., 2017Warfield L. Ramachandran S. Baptista T. Devys D. Tora L. Hahn S. Transcription of nearly all yeast RNA polymerase II-transcribed genes is dependent on transcription factor TFIID.Mol. Cell. 2017; 68: 118-129.e5Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). These studies showed that steady-state levels of yeast mRNAs are “buffered” when mRNA synthesis or degradation is affected by inactivation of either the transcription complexes required for mRNA synthesis or the enzymes responsible for cytoplasmic mRNA degradation, respectively. Decreases in transcription initiation are balanced by adjustments in global rates of mRNA degradation and vice versa, which then results in rather stable steady-state levels of most mRNAs (Figure 1). The molecular mechanisms underlying this balancing process are not well understood (Braun and Young, 2014Braun K.A. Young E.T. Coupling mRNA synthesis and decay.Mol. Cell. Biol. 2014; 34: 4078-4087Crossref PubMed Scopus (56) Google Scholar, Haimovich et al., 2013aHaimovich G. Choder M. Singer R.H. Trcek T. The fate of the messenger is pre-determined: a new model for regulation of gene expression.Biochim. Biophys. Acta. 2013; 1829: 643-653Crossref PubMed Scopus (74) Google Scholar). In this Perspective, we will discuss the diverse connections between the activities of the global transcription regulators in the nucleus and of the mRNA-degrading enzymes in the cytoplasm. We will describe experiments in yeast as the starting point of our discussion and will speculate on the nature of similar and alternative mechanisms sensing global mRNA levels in the context of mammalian cells. Understanding the mechanisms and signals of transcript buffering is not only of academic interest, but it has implications for the recent pharmacological interventions targeting global mRNA synthesis to reverse pathological conditions (Hou et al., 2018Hou Z.Y. Tong X.P. Peng Y.B. Zhang B.K. Yan M. Broad targeting of triptolide to resistance and sensitization for cancer therapy.Biomed. Pharmacother. 2018; 104: 771-780Crossref PubMed Scopus (30) Google Scholar, Kwiatkowski et al., 2014Kwiatkowski N. Zhang T. Rahl P.B. Abraham B.J. Reddy J. Ficarro S.B. Dastur A. Amzallag A. Ramaswamy S. Tesar B. et al.Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.Nature. 2014; 511: 616-620Crossref PubMed Scopus (536) Google Scholar, Wang et al., 2015Wang Y. Zhang T. Kwiatkowski N. Abraham B.J. Lee T.I. Xie S. Yuzugullu H. Von T. Li H. Lin Z. et al.CDK7-dependent transcriptional addiction in triple-negative breast cancer.Cell. 2015; 163: 174-186Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar). The central actors directing the initiation of mRNA synthesis are the Pol II enzyme, the basal transcription factors (such as TFIID), and co-activator complexes (such as Mediator and SAGA; Figure 2). Relevant for our discussion is that these complexes are conserved in structure and function throughout evolution. Promoter activation for Pol II transcription involves direct recruitment of the 25-subunit Mediator and the 19-subunit SAGA complexes by gene-specific activators. The Mediator complex is organized in a modular structure with the tail subunits responsible for activator interaction, and the middle and head modules dock onto Pol II to stabilize the pre-initiation complex (PIC) (Soutourina, 2018Soutourina J. Transcription regulation by the Mediator complex.Nat. Rev. Mol. Cell Biol. 2018; 19: 262-274Crossref PubMed Scopus (260) Google Scholar). The SAGA complex also displays a modular organization around the structural Spt20/Spt7/Taf core complex. The SAGA core is decorated with four modules of different functions: (1) activator interacting via the Tra1 subunit; (2) histone acetyltransferase (HAT), containing the Gcn5 enzyme together with three other subunits; (3) histone H2B deubiquitinase (DUB), containing the Ubp8 enzyme and three additional subunits; and (4) in yeast, the TATA-binding protein (TBP) interacting, containing the Spt3/Spt8 subunits (Helmlinger and Tora, 2017Helmlinger D. Tora L. Sharing the SAGA.Trends Biochem. Sci. 2017; 42: 850-861Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). The HAT, DUB, and TBP functions of SAGA are most relevant for global mRNA synthesis (Baptista et al., 2017Baptista T. Grünberg S. Minoungou N. Koster M.J.E. Timmers H.T.M. Hahn S. Devys D. Tora L. SAGA is a general cofactor for RNA polymerase II transcription.Mol. Cell. 2017; 68: 130-143.e5Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). Activators and co-activators participate in the recruitment of the TFIID complex to the promoters, which represents the first step of Pol II PIC assembly. TBP is an integral part of the TFIID complex, which also contains TBP-associated factors (TAFs) (14 in yeast and 13 in mammals). In yeast, core promoter binding by TFIID is directed in large part through canonical TATA elements or variants thereof (Rhee and Pugh, 2012Rhee H.S. Pugh B.F. Genome-wide structure and organization of eukaryotic pre-initiation complexes.Nature. 2012; 483: 295-301Crossref PubMed Scopus (347) Google Scholar). The subsequent and stepwise association of TFIIB, TFIIF/Pol II, TFIIE, and TFIIH completes the assembly of the full PIC (Thomas and Chiang, 2006Thomas M.C. Chiang C.M. The general transcription machinery and general cofactors.Crit. Rev. Biochem. Mol. Biol. 2006; 41: 105-178Crossref PubMed Scopus (614) Google Scholar). Open complex formation proceeds via separation of the two DNA strands at the transcription start site via the ATP-dependent DNA translocase activity of the Ssl2 subunit of TFIIH (XPB in human). TFIIH also harbors the cdk7/cyclin H kinase module for serine-5 phosphorylation of the Pol II-CTD (Compe and Egly, 2012Compe E. Egly J.M. TFIIH: when transcription met DNA repair.Nat. Rev. Mol. Cell Biol. 2012; 13: 343-354Crossref PubMed Scopus (230) Google Scholar, Heidemann et al., 2013Heidemann M. Hintermair C. Voß K. Eick D. Dynamic phosphorylation patterns of RNA polymerase II CTD during transcription.Biochim. Biophys. Acta. 2013; 1829: 55-62Crossref PubMed Scopus (182) Google Scholar). All subunits of the basal transcription machinery are encoded by essential yeast genes, with the interesting exception of Rpb4. These transcription regulatory complexes are all involved in transcript buffering in yeast. This was first revealed by examination of the Mediator subunit Med17/Srb4 and two Pol II subunits: Rpb1 and Rpb4 (Schulz et al., 2014Schulz D. Pirkl N. Lehmann E. Cramer P. Rpb4 subunit functions mainly in mRNA synthesis by RNA polymerase II.J. Biol. Chem. 2014; 289: 17446-17452Crossref PubMed Scopus (30) Google Scholar, Sun et al., 2012Sun M. Schwalb B. Schulz D. Pirkl N. Etzold S. Larivière L. Maier K.C. Seizl M. Tresch A. Cramer P. Comparative dynamic transcriptome analysis (cDTA) reveals mutual feedback between mRNA synthesis and degradation.Genome Res. 2012; 22: 1350-1359Crossref PubMed Scopus (179) Google Scholar). In addition, recent work showed that mRNA synthesis displays a similar global dependence on the SAGA co-activator, the basal factor TFIID, and the CTD-kinase activity of TFIIH (Baptista et al., 2017Baptista T. Grünberg S. Minoungou N. Koster M.J.E. Timmers H.T.M. Hahn S. Devys D. Tora L. SAGA is a general cofactor for RNA polymerase II transcription.Mol. Cell. 2017; 68: 130-143.e5Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, Rodríguez-Molina et al., 2016Rodríguez-Molina J.B. Tseng S.C. Simonett S.P. Taunton J. Ansari A.Z. Engineered covalent inactivation of TFIIH-kinase reveals an elongation checkpoint and results in widespread mRNA stabilization.Mol. Cell. 2016; 63: 433-444Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, Warfield et al., 2017Warfield L. Ramachandran S. Baptista T. Devys D. Tora L. Hahn S. Transcription of nearly all yeast RNA polymerase II-transcribed genes is dependent on transcription factor TFIID.Mol. Cell. 2017; 68: 118-129.e5Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). These results are surprising in light of earlier studies, which indicated restricted promoter binding by TFIID and SAGA and a differential transcriptional dependence on these complexes for subsets of yeast genes (Huisinga and Pugh, 2004Huisinga K.L. Pugh B.F. A genome-wide housekeeping role for TFIID and a highly regulated stress-related role for SAGA in Saccharomyces cerevisiae.Mol. Cell. 2004; 13: 573-585Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar, Lee et al., 2000Lee T.I. Causton H.C. Holstege F.C. Shen W.C. Hannett N. Jennings E.G. Winston F. Green M.R. Young R.A. Redundant roles for the TFIID and SAGA complexes in global transcription.Nature. 2000; 405: 701-704Crossref PubMed Scopus (299) Google Scholar, Shen et al., 2003Shen W.C. Bhaumik S.R. Causton H.C. Simon I. Zhu X. Jennings E.G. Wang T.H. Young R.A. Green M.R. Systematic analysis of essential yeast TAFs in genome-wide transcription and preinitiation complex assembly.EMBO J. 2003; 22: 3395-3402Crossref PubMed Scopus (80) Google Scholar). In the earlier studies, decreases in global transcription were masked due to the analysis of the steady-state mRNAs. The recent studies used the comparative dynamic transcriptome analysis (cDTA) (Sun et al., 2012Sun M. Schwalb B. Schulz D. Pirkl N. Etzold S. Larivière L. Maier K.C. Seizl M. Tresch A. Cramer P. Comparative dynamic transcriptome analysis (cDTA) reveals mutual feedback between mRNA synthesis and degradation.Genome Res. 2012; 22: 1350-1359Crossref PubMed Scopus (179) Google Scholar), which relies on in vivo pulse labeling of RNA with 4-thiouracil (4sU) followed by simultaneous measurements of purified newly synthesized RNA, compared to total mRNA and normalized by spike-in controls. Combined with values of mRNA half-lives, cDTA provides synthesis and degradation rates for individual mRNAs as well as the level of total mRNA. Subjecting gene deletion or depletion strains of the basal transcription machinery to cDTA revealed that a reduced global transcription is balanced by lower mRNA degradation rates across the board. Although the magnitudes of changes differ between subunits of Pol II, TFIID, SAGA, or Mediator, the fold changes in synthesis and degradation are strikingly similar (see Table 1). The net result is an efficient transcript buffering to maintain similar cellular concentrations of mRNA. Time course analyses of selected genes after depletion of the SAGA subunit Spt7 or the Med17/Srb4 or Med18 subunits of the middle Mediator module show a rapid reduction of mRNA synthesis, resulting in a temporary reduction of total mRNA at 15 min of depletion, which is completely buffered by decreased rates of degradation after 60 min (Baptista et al., 2017Baptista T. Grünberg S. Minoungou N. Koster M.J.E. Timmers H.T.M. Hahn S. Devys D. Tora L. SAGA is a general cofactor for RNA polymerase II transcription.Mol. Cell. 2017; 68: 130-143.e5Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, Plaschka et al., 2015Plaschka C. Larivière L. Wenzeck L. Seizl M. Hemann M. Tegunov D. Petrotchenko E.V. Borchers C.H. Baumeister W. Herzog F. et al.Architecture of the RNA polymerase II-Mediator core initiation complex.Nature. 2015; 518: 376-380Crossref PubMed Scopus (210) Google Scholar, Sun et al., 2013Sun M. Schwalb B. Pirkl N. Maier K.C. Schenk A. Failmezger H. Tresch A. Cramer P. Global analysis of eukaryotic mRNA degradation reveals Xrn1-dependent buffering of transcript levels.Mol. Cell. 2013; 52: 52-62Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). This indicates that transcript buffering in yeast is a relatively rapid process with a lag phase of 15–30 min. The nature of the signal emanating from the inactivation of global transcription complexes in the nucleus that is perceived by the cytoplasmic mRNA degradation machinery requires further investigation.Table 1Yeast Genes Tested for Transcript Buffering by cDTA Using Deletion, Conditional Depletion, or Mutant StrainsComplexSubunit Tested by cDTASynthesis RateDegradation RateBufferingReferencePol IIRpb1-N488D0.260.31Y(Sun et al., 2012Sun M. Schwalb B. Schulz D. Pirkl N. Etzold S. Larivière L. Maier K.C. Seizl M. Tresch A. Cramer P. Comparative dynamic transcriptome analysis (cDTA) reveals mutual feedback between mRNA synthesis and degradation.Genome Res. 2012; 22: 1350-1359Crossref PubMed Scopus (179) Google Scholar)Rbp40.120.09Y(Schulz et al., 2014Schulz D. Pirkl N. Lehmann E. Cramer P. Rpb4 subunit functions mainly in mRNA synthesis by RNA polymerase II.J. Biol. Chem. 2014; 289: 17446-17452Crossref PubMed Scopus (30) Google Scholar)TFIIDTaf40.370.55Y(Warfield et al., 2017Warfield L. Ramachandran S. Baptista T. Devys D. Tora L. Hahn S. Transcription of nearly all yeast RNA polymerase II-transcribed genes is dependent on transcription factor TFIID.Mol. Cell. 2017; 68: 118-129.e5Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar)TFIIHKin28/Cdk70.3n.d.Y(Rodríguez-Molina et al., 2016Rodríguez-Molina J.B. Tseng S.C. Simonett S.P. Taunton J. Ansari A.Z. Engineered covalent inactivation of TFIIH-kinase reveals an elongation checkpoint and results in widespread mRNA stabilization.Mol. Cell. 2016; 63: 433-444Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar)SAGASpt70.260.34Y(Baptista et al., 2017Baptista T. Grünberg S. Minoungou N. Koster M.J.E. Timmers H.T.M. Hahn S. Devys D. Tora L. SAGA is a general cofactor for RNA polymerase II transcription.Mol. Cell. 2017; 68: 130-143.e5Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar)Spt200.230.29Y(Baptista et al., 2017Baptista T. Grünberg S. Minoungou N. Koster M.J.E. Timmers H.T.M. Hahn S. Devys D. Tora L. SAGA is a general cofactor for RNA polymerase II transcription.Mol. Cell. 2017; 68: 130-143.e5Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar)Gcn50.650.59Y(Baptista et al., 2017Baptista T. Grünberg S. Minoungou N. Koster M.J.E. Timmers H.T.M. Hahn S. Devys D. Tora L. SAGA is a general cofactor for RNA polymerase II transcription.Mol. Cell. 2017; 68: 130-143.e5Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar)Spt30.520.43Y(Baptista et al., 2017Baptista T. Grünberg S. Minoungou N. Koster M.J.E. Timmers H.T.M. Hahn S. Devys D. Tora L. SAGA is a general cofactor for RNA polymerase II transcription.Mol. Cell. 2017; 68: 130-143.e5Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar)Spt81.151.08-(Baptista et al., 2017Baptista T. Grünberg S. Minoungou N. Koster M.J.E. Timmers H.T.M. Hahn S. Devys D. Tora L. SAGA is a general cofactor for RNA polymerase II transcription.Mol. Cell. 2017; 68: 130-143.e5Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar)Ubp80.950.86-(Baptista et al., 2017Baptista T. Grünberg S. Minoungou N. Koster M.J.E. Timmers H.T.M. Hahn S. Devys D. Tora L. SAGA is a general cofactor for RNA polymerase II transcription.Mol. Cell. 2017; 68: 130-143.e5Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar)Gcn5/Spt30.100.17Y(Baptista et al., 2017Baptista T. Grünberg S. Minoungou N. Koster M.J.E. Timmers H.T.M. Hahn S. Devys D. Tora L. SAGA is a general cofactor for RNA polymerase II transcription.Mol. Cell. 2017; 68: 130-143.e5Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar)Gcn5/Ubp80.510.47Y(Baptista et al., 2017Baptista T. Grünberg S. Minoungou N. Koster M.J.E. Timmers H.T.M. Hahn S. Devys D. Tora L. SAGA is a general cofactor for RNA polymerase II transcription.Mol. Cell. 2017; 68: 130-143.e5Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar)MediatorMed17/Srb40.060.07Y(Plaschka et al., 2015Plaschka C. Larivière L. Wenzeck L. Seizl M. Hemann M. Tegunov D. Petrotchenko E.V. Borchers C.H. Baumeister W. Herzog F. et al.Architecture of the RNA polymerase II-Mediator core initiation complex.Nature. 2015; 518: 376-380Crossref PubMed Scopus (210) Google Scholar)Med180.570.46Y(Plaschka et al., 2015Plaschka C. Larivière L. Wenzeck L. Seizl M. Hemann M. Tegunov D. Petrotchenko E.V. Borchers C.H. Baumeister W. Herzog F. et al.Architecture of the RNA polymerase II-Mediator core initiation complex.Nature. 2015; 518: 376-380Crossref PubMed Scopus (210) Google Scholar)Xrn1Xrn11.60.49N(Sun et al., 2013Sun M. Schwalb B. Pirkl N. Maier K.C. Schenk A. Failmezger H. Tresch A. Cramer P. Global analysis of eukaryotic mRNA degradation reveals Xrn1-dependent buffering of transcript levels.Mol. Cell. 2013; 52: 52-62Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar)Ccr4/NotCcr40.490.45Y(Sun et al., 2012Sun M. Schwalb B. Schulz D. Pirkl N. Etzold S. Larivière L. Maier K.C. Seizl M. Tresch A. Cramer P. Comparative dynamic transcriptome analysis (cDTA) reveals mutual feedback between mRNA synthesis and degradation.Genome Res. 2012; 22: 1350-1359Crossref PubMed Scopus (179) Google Scholar)Pop2/Caf10.740.33Y(Sun et al., 2013Sun M. Schwalb B. Pirkl N. Maier K.C. Schenk A. Failmezger H. Tresch A. Cramer P. Global analysis of eukaryotic mRNA degradation reveals Xrn1-dependent buffering of transcript levels.Mol. Cell. 2013; 52: 52-62Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar)Not30.890.83-(Sun et al., 2013Sun M. Schwalb B. Pirkl N. Maier K.C. Schenk A. Failmezger H. Tresch A. Cramer P. Global analysis of eukaryotic mRNA degradation reveals Xrn1-dependent buffering of transcript levels.Mol. Cell. 2013; 52: 52-62Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar)Caf400.850.53Y(Sun et al., 2013Sun M. Schwalb B. Pirkl N. Maier K.C. Schenk A. Failmezger H. Tresch A. Cramer P. Global analysis of eukaryotic mRNA degradation reveals Xrn1-dependent buffering of transcript levels.Mol. Cell. 2013; 52: 52-62Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar)Lsm-Pat1Lsm11.110.89-(Sun et al., 2013Sun M. Schwalb B. Pirkl N. Maier K.C. Schenk A. Failmezger H. Tresch A. Cramer P. Global analysis of eukaryotic mRNA degradation reveals Xrn1-dependent buffering of transcript levels.Mol. Cell. 2013; 52: 52-62Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar)Lsm60.990.80-(Sun et al., 2013Sun M. Schwalb B. Pirkl N. Maier K.C. Schenk A. Failmezger H. Tresch A. Cramer P. Global analysis of eukaryotic mRNA degradation reveals Xrn1-dependent buffering of transcript levels.Mol. Cell. 2013; 52: 52-62Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar)Lsm71.000.98-(Sun et al., 2013Sun M. Schwalb B. Pirkl N. Maier K.C. Schenk A. Failmezger H. Tresch A. Cramer P. Global analysis of eukaryotic mRNA degradation reveals Xrn1-dependent buffering of transcript levels.Mol. Cell. 2013; 52: 52-62Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar)Pat10.380.60Y(Sun et al., 2013Sun M. Schwalb B. Pirkl N. Maier K.C. Schenk A. Failmezger H. Tresch A. Cramer P. Global analysis of eukaryotic mRNA degradation reveals Xrn1-dependent buffering of transcript levels.Mol. Cell. 2013; 52: 52-62Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar)ExosomeRrp60.600.52Y(Sun et al., 2013Sun M. Schwalb B. Pirkl N. Maier K.C. Schenk A. Failmezger H. Tresch A. Cramer P. Global analysis of eukaryotic mRNA degradation reveals Xrn1-dependent buffering of transcript levels.Mol. Cell. 2013; 52: 52-62Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar)Rrp47/Lrp10.400.43Y(Sun et al., 2013Sun M. Schwalb B. Pirkl N. Maier K.C. Schenk A. Failmezger H. Tresch A. Cramer P. Global analysis of eukaryotic mRNA degradation reveals Xrn1-dependent buffering of transcript levels.Mol. Cell. 2013; 52: 52-62Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar)Yeast genes analyzed for changes in mRNA synthesis and degradation. The values for global synthesis and degradation rates are depicted as linear ratios of mutant over the isogenic wild-type strain. These values are taken from the indicated studies. Transcript buffering was judged positive (Y) when both the synthesis and degradation rates differed to a similar extent and more than 15% from the corresponding wild-type values. No buffering (N) was observed for the xrn1 deletion as mRNA degradation is decreased and mRNA synthesis is increased. (-) indicates that the effects on synthesis and degradation rates were minimal. n.d., not determined. Open table in a new tab Yeast genes analyzed for changes in mRNA synthesis and degradation. The values for global synthesis and degradation rates are depicted as linear ratios of mutant over the isogenic wild-type strain. These values are taken from the indicated studies. Transcript buffering was judged positive (Y) when both the synthesis and degradation rates differed to a similar extent and more than 15% from the corresponding wild-type values. No buffering (N) was observed for the xrn1 deletion as mRNA degradation is decreased and mRNA synthesis is increased. (-) indicates that the effects on synthesis and degradation rates were minimal. n.d., not determined. The cDTA approach was pioneered originally to investigate the involvement of mRNA degradation enzymes in controlling mRNA levels in yeast cells (Sun et al., 2012Sun M. Schwalb B. Schulz D. Pirkl N. Etzold S. Larivière L. Maier K.C. Seizl M. Tresch A. Cramer P. Comparative dynamic transcriptome analysis (cDTA) reveals mutual feedback between mRNA synthesis and degradation.Genome Res. 2012; 22: 1350-1359Crossref PubMed Scopus (179) Google Scholar, Sun et al., 2013Sun M. Schwalb B. Pirkl N. Maier K.C. Schenk A. Failmezger H. Tresch A. Cramer P. Global analysis of eukaryotic mRNA degradation reveals Xrn1-dependent buffering of transcript levels.Mol. Cell. 2013; 52: 52-62Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). In its basic outline, the default mRNA degradation pathway of yeast (Figure 2) is very similar to its mammalian counterpart. Before we summarize their involvement in transcript buffering, we will first describe the components of the default pathway. The initiation of mRNA degradation starts with destabilization of the mRNA loop structure required for efficient translation (Łabno et al., 2016Łabno A. Tomecki R. Dziembowski A. Cytoplasmic RNA decay pathways - enzymes and mechanisms.Biochim. Biophys. Acta. 2016; 1863: 3125-3147Crossref PubMed Scopus (110) Google Scholar). This closed mRNA loop is formed by interactions between the cap-binding proteins like eIF4E at its 5′ end and poly(A)-binding proteins (PABPs) (Pab1 in yeast or PABPN1-5 and PABPC1-5 in humans) associated to the 3′ end. For the majority of mRNAs, loop destabilization involves shortening of the poly(A) tail, resulting in loss of Pab1 binding. The short tail can result in activation of the Lsm1-7/Pat1 complex, which in turn stimulates Dcp1/Dcp2-mediated cap hydrolysis from the 5′ end of the mRNA. Cap removal by Dcp1/Dcp2 is stimulated by the Dhh1 RNA helicase (DDX6 in humans) and Ecd proteins. The unprotected 5′ end is now a substrate for the Xrn1 exonuclease, which acts in the 5′–3′ direction. Alternatively, the short oligo(A) tail is captured by the exosome, which degrades mRNAs from their 3′ end (Łabno et al., 2016Łabno A. Tomecki R. Dziembowski A. Cytoplasmic RNA decay pathways - enzymes and mechanisms.Biochim. Biophys. Acta. 2016; 1863: 3125-3147Crossref PubMed Scopus (110) Google Scholar). In both pathways, deadenyl" @default.
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