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• W1976425824 abstract "RNA polymerase (RNAP) II is subject to extensive phosphorylation on the heptapeptide repeats of the C-terminal domain (CTD) of the largest subunit. An activity that is required for the dephosphorylation of yeast RNAP II in vitro has been purified from a yeast whole cell extract by >30,000-fold. The yeast CTD phosphatase activity copurified with two bands with apparent molecular masses of 100 and 103 kDa. The properties of the yeast CTD phosphatase are similar to those of a previously characterized CTD phosphatase from HeLa cells. These properties include stimulation by the general transcription factor IIF (TFIIF), competitive inhibition by RNAP II, magnesium dependence, and resistance to okadaic acid. Both the HeLa and yeast CTD phosphatases are highly specific for their cognate polymerases. Neither phosphatase functions upon the polymerase molecule from the other species, even though the heptapeptide repeats of the CTDs in yeast RNAP II and mammalian RNAP II are essentially identical. The activity of the highly purified CTD phosphatase is stimulated >300-fold by a partially purified fraction of TFIIF. Recombinant TFIIF did not substitute for the TFIIF fraction, indicating that an additional factor present in the TFIIF fraction is required for CTD phosphatase activity. These results show that yeast contains a CTD phosphatase activity similar to that of mammalian cells that is likely composed of at least two components, one of which is 100 and/or 103 kDa. RNA polymerase (RNAP) II is subject to extensive phosphorylation on the heptapeptide repeats of the C-terminal domain (CTD) of the largest subunit. An activity that is required for the dephosphorylation of yeast RNAP II in vitro has been purified from a yeast whole cell extract by >30,000-fold. The yeast CTD phosphatase activity copurified with two bands with apparent molecular masses of 100 and 103 kDa. The properties of the yeast CTD phosphatase are similar to those of a previously characterized CTD phosphatase from HeLa cells. These properties include stimulation by the general transcription factor IIF (TFIIF), competitive inhibition by RNAP II, magnesium dependence, and resistance to okadaic acid. Both the HeLa and yeast CTD phosphatases are highly specific for their cognate polymerases. Neither phosphatase functions upon the polymerase molecule from the other species, even though the heptapeptide repeats of the CTDs in yeast RNAP II and mammalian RNAP II are essentially identical. The activity of the highly purified CTD phosphatase is stimulated >300-fold by a partially purified fraction of TFIIF. Recombinant TFIIF did not substitute for the TFIIF fraction, indicating that an additional factor present in the TFIIF fraction is required for CTD phosphatase activity. These results show that yeast contains a CTD phosphatase activity similar to that of mammalian cells that is likely composed of at least two components, one of which is 100 and/or 103 kDa. INTRODUCTIONThe largest subunit of RNAP 1The abbreviations used are: RNAPRNA polymeraseCTDC-terminal domainTFtranscription factorDTTdithiothreitolPAGEpolyacrylamide gel electrophoresis. II contains a highly conserved C-terminal domain composed of multiple heptapeptide repeats with the consensus sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7 (1Dahmus M.E. Prog. Nucleic Acids Res. 1994; 48: 143-179Google Scholar). The number of repeats varies in different organisms, with 26 in yeast and 52 in mammals. The exact function of the CTD in transcription is not clear. Genetic studies have shown the CTD to be essential in vivo; however, yeast can tolerate deletions leaving a minimum of eight repeats (2West M.L. Corden J.L. Genetics. 1995; 140: 1223-1233Google Scholar). In vitro, the CTD is not required in a reconstituted transcription system with the adenovirus major late promoter (3Kim W.-Y. Dahmus M.E. J. Biol. Chem. 1989; 264: 3169-3176Google Scholar), but is required at promoters lacking a consensus TATA sequence (4Kang M.E. Dahmus M.E. J. Biol. Chem. 1993; 268: 25033-25040Google Scholar, 5Buermeyer A.B. Strasheim L.A. McMahon S.L. Farnham P.J. J. Biol. Chem. 1995; 270: 6798-6807Google Scholar). The CTD interacts with a variety of transcription factors in vitro, including TATA-binding protein, TFIIF, TFIIE, and the SRB complex (6Usheva A. Maldonado E. Goldring A. Lu H. Houbavi C. Reinberg D. Aloni Y. Cell. 1992; 69: 871-881Google Scholar, 7Kang M.E. Dahmus M.E. J. Biol. Chem. 1995; 270: 23390-23397Google Scholar, 8Thompson C.M. Koleske A.J. Chao D.M. Young R.A. Cell. 1993; 73: 1361-1375Google Scholar). The association of the SRB complex and other factors with RNAP II forms what has been termed the holoenzyme. This complex is thought to be recruited to promoters in vivo and to mediate activated transcription (9Koleske A.J. Young R.A. Nature. 1994; 368: 466-469Google Scholar).The CTD is subject to extensive phosphorylation in vivo, with a stoichiometry of approximately one phosphate per repeat (1Dahmus M.E. Prog. Nucleic Acids Res. 1994; 48: 143-179Google Scholar). Phosphorylation predominantly occurs on serine residues, with small amounts on threonine and tyrosine residues. The unphosphorylated form of RNAP II is designated RNAP IIA, whereas the phosphorylated form is designated RNAP IIO. A variety of studies have shown that RNAP IIA and RNAP IIO have distinct functions during transcription and that each round of transcription is associated with the reversible phosphorylation of the CTD. RNAP IIA preferentially assembles into a preinitiation complex with transcription factors on promoter DNA (10Chesnut J.D. Stephens J.H. Dahmus M.E. J. Biol. Chem. 1992; 267: 10500-10506Google Scholar), whereas elongation of the transcript is almost exclusively catalyzed by RNAP IIO (11Cadena D.L. Dahmus M.E. J. Biol. Chem. 1987; 262: 12468-12474Google Scholar). Phosphorylation of RNAP IIA occurs sometime during the initiation of transcription and is thought to trigger the release of RNAP II from the preinitiation complex (12Laybourn P.J. Dahmus M.E. J. Biol. Chem. 1990; 265: 13165-13173Google Scholar). RNAP IIO is presumably dephosphorylated at or after termination of transcription to regenerate RNAP IIA for the next round of transcription. CTD phosphorylation appears to be an important mechanism in regulating RNAP II activity in vivo, and changes in the phosphorylation state of RNAP II are associated with major changes in the pattern of transcription. For example, serum stimulation of quiescent cells, heat shock, and viral infection all dramatically alter cellular transcription and also result in a change in the phosphorylation state of RNAP II (13Dubois M.F. Bellier S. Seo S.J. Bensaude O. J. Cell. Physiol. 1994; 158: 417-426Google Scholar, 14Dubois M.F. Nguyen V.T. Dahmus M.E. Pages G. Pouyssegar J. Bensaude O. EMBO J. 1994; 13: 4787-4797Google Scholar, 15Rice S.A. Long M.C. Lam V. Spencer C.A. J. Virol. 1994; 68: 988-1001Google Scholar).Many different protein kinases have been characterized that can phosphorylate the CTD in vitro. Two yeast protein kinases, CTK1 and KIN28, have been shown to be important for phosphorylation of RNAP II in vivo. Disruption of the CTK1 gene results in a large decrease in RNAP II phosphorylation in vivo (16Lee J.M. Greenleaf A.L. Gene Expr. 1991; 1: 149-167Google Scholar). The null mutant ctk1 cells, although viable, exhibit slow growth and other phenotypes, but it is not known what role CTK1 has in transcription. The KIN28 kinase is found associated with the general transcription factor IIH, which assembles into the preinitiation complex (17Feaver W.J. Svejstrup J.Q. Henry N.L. Kornberg R.D. Cell. 1994; 79: 1103-1109Google Scholar). The KIN28 gene is essential, and loss of the KIN28 kinase activity results in a dramatic decrease in RNAP II phosphorylation and transcriptional activity (18Valay J.G. Simon M. Dubois M.F. Bensaude O. Facca C. Faye G. J. Mol. Biol. 1995; 249: 535-544Google Scholar).Much less is known about CTD phosphatases. A CTD phosphatase activity has been purified from HeLa cells that is highly specific for RNAP II and dephosphorylates the CTD processively (19Chambers R.S. Dahmus M.E. J. Biol. Chem. 1994; 269: 26243-26248Google Scholar). Two proteins with apparent molecular masses of 205 and 150 kDa copurify with the HeLa CTD phosphatase activity, although it is not clear which contains the catalytic activity. In contrast to CTD kinases, HeLa CTD phosphatase does not use recombinant CTD as a substrate (20Chambers R.S. Wang B.Q. Burton Z.F. Dahmus M.E. J. Biol. Chem. 1995; 270: 14962-14969Google Scholar). Furthermore, CTD phosphatase is competitively inhibited by RNAP IIB, a form of RNAP II that lacks the CTD. These and other results suggested that a docking site exists on RNAP II that CTD phosphatase must first bind before it can gain access to the CTD. HeLa CTD phosphatase is also stimulated 5-fold by TFIIF, and the stimulation can be inhibited by TFIIB. The minimal region of TFIIF sufficient to stimulate CTD phosphatase is the C-terminal 160 amino acids of the RAP74 subunit (20Chambers R.S. Wang B.Q. Burton Z.F. Dahmus M.E. J. Biol. Chem. 1995; 270: 14962-14969Google Scholar).Serine/threonine protein phosphatases have been classified into four families, PP1, PP2A, PP2B, and PP2C, based on biochemical properties and amino acid sequence (21Cohen P. Annu. Rev. Biochem. 1989; 58: 453-508Google Scholar). PP1, PP2A, and PP2B are all inhibited by okadaic acid, although with differing sensitivities. PP2B requires calcium ions for activity, and PP2C requires magnesium ions. HeLa CTD phosphatase has been classified as a type 2C phosphatase based on its requirement for magnesium ions and its resistance to okadaic acid. This report describes the purification and characterization of a type 2C phosphatase from yeast specific for the CTD of RNAP II.DISCUSSIONYeast contains a protein phosphatase activity that is highly specific for dephosphorylating the largest subunit of yeast RNAP II. Many of the properties of the yeast CTD phosphatase are similar to those of the HeLa enzyme (19Chambers R.S. Dahmus M.E. J. Biol. Chem. 1994; 269: 26243-26248Google Scholar). These similarities include specificity for RNAP II as a substrate, stimulation of activity by the general transcription factor IIF, inhibition by excess RNAP II, resistance to the phosphatase inhibitor okadaic acid, requirement for magnesium ions for activity, and inhibition by high concentrations of salt (19Chambers R.S. Dahmus M.E. J. Biol. Chem. 1994; 269: 26243-26248Google Scholar). The magnesium requirement and resistance to okadaic acid would characterize the yeast CTD phosphatase, like the HeLa enzyme, as a type 2C phosphatase. However, the yeast CTD phosphatase activity is also supported by calcium ions, a property not seen before in the type 2C class of enzymes (21Cohen P. Annu. Rev. Biochem. 1989; 58: 453-508Google Scholar). The HeLa CTD phosphatase cannot use calcium ions to support activity, but can use zinc, which did not support activity with the yeast enzyme. Other magnesium-dependent phosphatases are unaffected by calcium, inhibited (34Wang Y. Santini F. Qin K. Huang C.Y. J. Biol. Chem. 1995; 270: 25607-25612Google Scholar), or stimulated (35Lawson J.E. Niu X.D. Browning K.S. Trong H.L. Yan J. Reed L.J. Biochemistry. 1993; 32: 8987-8993Google Scholar). Millimolar amounts of calcium are required for significant activity of the yeast CTD phosphatase, and calcium does not support a level of activity higher than with magnesium alone. Thus, the enzyme is unlikely to be regulated by calcium in vivo. However, this unusual property could be used to distinguish it from other phosphatases in whole cell extracts.There appears to be a strict species specificity between each phosphatase and its cognate polymerase. The yeast and HeLa CTD phosphatases failed to dephosphorylate RNAP II from the other species. This species specificity is surprising since the heptapeptide repeats of the CTDs of yeast RNAP II and mammalian RNAP II are essentially identical. Previous studies with the HeLa CTD phosphatase indicated that there is a docking site on RNAP II distinct from the CTD where CTD phosphatase must interact before dephosphorylating the CTD (20Chambers R.S. Wang B.Q. Burton Z.F. Dahmus M.E. J. Biol. Chem. 1995; 270: 14962-14969Google Scholar). The species specificity is likely due to divergent protein structures at the docking site between the yeast and mammalian RNAP II molecules. Work directed toward identifying the subunit(s) of RNAP II important for interacting with CTD phosphatase is underway. Yeast RNAP II lacking either subunits 4 and 7 (25Edwards A.M. Kane C.M. Young R.A. Kornberg R.D. J. Biol. Chem. 1991; 266: 71-75Google Scholar) or subunit 9 (26Woychik N.A. Lane W.S. Young R.A. J. Biol. Chem. 1991; 266: 19053-19055Google Scholar) is dephosphorylated with equal efficiency compared with wild-type RNAP II.2There is an additional level of species specificity in CTD phosphatase function and that concerns the stimulation by TFIIF. The yeast and HeLa CTD phosphatases are stimulated only by their cognate TFIIF molecules, i.e. human TFIIF cannot stimulate yeast CTD phosphatase activity with either yeast or mammalian RNAP II. The HeLa CTD phosphatase has been shown to bind to human TFIIF and RAP74 deletion constructs immobilized on Ni2+-nitrilotriacetic acid-agarose beads, and the binding interaction requires the C-terminal 160 amino acids of RAP74. 3R. S. Chambers and M. E. Dahmus, unpublished observations. Thus, at least two protein-protein interactions are likely to be important for efficient phosphatase activity, phosphatase with RNAP II and phosphatase with TFIIF. Human TFIIF functions with Drosophila RNAP II in an in vitro transcription elongation system (36Kephart D.D. Wang B.Q. Burton Z.F. Price D.H. J. Biol. Chem. 1994; 269: 13536-13543Google Scholar), and TFIIF from Schizosaccharomyces pombe and that from Saccharomyces cerevisiae are functionally interchangeable in a heterologous in vitro transcription system (37Li Y. Flanagan P.M. Tschochner H. Kornberg R.D. Science. 1994; 263: 805-807Google Scholar). However, Saccharomyces TFIIF does not function with mammalian RNAP II and transcription factors in an in vitro transcription assay. 4J. W. Conaway, personal communication. The highly purified yeast CTD phosphatase activity is stimulated >300-fold by an SP-Sepharose fraction from the CTD phosphatase purification that contains TFIIF. Highly purified HeLa CTD phosphatase is stimulated only 5-fold by recombinant human TFIIF (20Chambers R.S. Wang B.Q. Burton Z.F. Dahmus M.E. J. Biol. Chem. 1995; 270: 14962-14969Google Scholar). Surprisingly, recombinant yeast TFIIF did not stimulate highly purified yeast CTD phosphatase, but did stimulate partially purified fractions of CTD phosphatase. These results suggest that an additional essential factor for CTD phosphatase activity is fractionated from the 100/103-kDa component at the SP-Sepharose column step in the purification. If mammalian CTD phosphatase requires a similar factor, then it must remain stably associated since the HeLa enzyme showed no dramatic decline in activity after many purification steps and was not dependent on other fractions for activity (19Chambers R.S. Dahmus M.E. J. Biol. Chem. 1994; 269: 26243-26248Google Scholar). This difference in purified complexes might be analogous to the differential stability seen with TATA-binding protein- TATA-binding protein-associated factor complexes, which are stable in mammalian extracts, but dissociate during purification in yeast (38Poon D. Weil P.A. J. Biol. Chem. 1993; 268: 15325-15328Google Scholar).SDS-PAGE analysis of the highly purified yeast CTD phosphatase shows two bands with apparent molecular masses of 100 and 103 kDa. Glycerol gradient sedimentation and gel filtration analysis indicate a monomeric structure with an elongated shape. It is not clear if the two proteins represent two different forms of CTD phosphatase or if one of them is an unrelated protein. Microsequences from three peptides derived from the 100/103-kDa proteins match a single yeast gene of previously unknown function, predicting a highly acidic protein with a molecular mass of 83 kDa. 5J. Archambault, R. S. Chambers, G. Pan, M. Kobor, B. Andrews, C. M. Kane, and J. Greenblatt, manuscript in preparation. The yeast genome sequence data base contains five genes with homology to type 2C phosphatases with predicted molecular masses ranging from 32 to 64 kDa. None of these has detectable similarity to the 83-kDa protein. Since serine/threonine protein phosphatases are a highly conserved family of enzymes, the lack of detectable homology of the gene encoding the 83-kDa protein to other phosphatases presents two possibilities. The 83-kDa protein may represent a new specific class of protein phosphatases. Alternatively, this protein may have a regulatory role in CTD phosphatase function. The isolation and characterization of CTD phosphatase from yeast now allow a combined biochemical and genetic analysis to distinguish these possibilities. In addition, the function of this enzyme during transcription can now be examined in detail. INTRODUCTIONThe largest subunit of RNAP 1The abbreviations used are: RNAPRNA polymeraseCTDC-terminal domainTFtranscription factorDTTdithiothreitolPAGEpolyacrylamide gel electrophoresis. II contains a highly conserved C-terminal domain composed of multiple heptapeptide repeats with the consensus sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7 (1Dahmus M.E. Prog. Nucleic Acids Res. 1994; 48: 143-179Google Scholar). The number of repeats varies in different organisms, with 26 in yeast and 52 in mammals. The exact function of the CTD in transcription is not clear. Genetic studies have shown the CTD to be essential in vivo; however, yeast can tolerate deletions leaving a minimum of eight repeats (2West M.L. Corden J.L. Genetics. 1995; 140: 1223-1233Google Scholar). In vitro, the CTD is not required in a reconstituted transcription system with the adenovirus major late promoter (3Kim W.-Y. Dahmus M.E. J. Biol. Chem. 1989; 264: 3169-3176Google Scholar), but is required at promoters lacking a consensus TATA sequence (4Kang M.E. Dahmus M.E. J. Biol. Chem. 1993; 268: 25033-25040Google Scholar, 5Buermeyer A.B. Strasheim L.A. McMahon S.L. Farnham P.J. J. Biol. Chem. 1995; 270: 6798-6807Google Scholar). The CTD interacts with a variety of transcription factors in vitro, including TATA-binding protein, TFIIF, TFIIE, and the SRB complex (6Usheva A. Maldonado E. Goldring A. Lu H. Houbavi C. Reinberg D. Aloni Y. Cell. 1992; 69: 871-881Google Scholar, 7Kang M.E. Dahmus M.E. J. Biol. Chem. 1995; 270: 23390-23397Google Scholar, 8Thompson C.M. Koleske A.J. Chao D.M. Young R.A. Cell. 1993; 73: 1361-1375Google Scholar). The association of the SRB complex and other factors with RNAP II forms what has been termed the holoenzyme. This complex is thought to be recruited to promoters in vivo and to mediate activated transcription (9Koleske A.J. Young R.A. Nature. 1994; 368: 466-469Google Scholar).The CTD is subject to extensive phosphorylation in vivo, with a stoichiometry of approximately one phosphate per repeat (1Dahmus M.E. Prog. Nucleic Acids Res. 1994; 48: 143-179Google Scholar). Phosphorylation predominantly occurs on serine residues, with small amounts on threonine and tyrosine residues. The unphosphorylated form of RNAP II is designated RNAP IIA, whereas the phosphorylated form is designated RNAP IIO. A variety of studies have shown that RNAP IIA and RNAP IIO have distinct functions during transcription and that each round of transcription is associated with the reversible phosphorylation of the CTD. RNAP IIA preferentially assembles into a preinitiation complex with transcription factors on promoter DNA (10Chesnut J.D. Stephens J.H. Dahmus M.E. J. Biol. Chem. 1992; 267: 10500-10506Google Scholar), whereas elongation of the transcript is almost exclusively catalyzed by RNAP IIO (11Cadena D.L. Dahmus M.E. J. Biol. Chem. 1987; 262: 12468-12474Google Scholar). Phosphorylation of RNAP IIA occurs sometime during the initiation of transcription and is thought to trigger the release of RNAP II from the preinitiation complex (12Laybourn P.J. Dahmus M.E. J. Biol. Chem. 1990; 265: 13165-13173Google Scholar). RNAP IIO is presumably dephosphorylated at or after termination of transcription to regenerate RNAP IIA for the next round of transcription. CTD phosphorylation appears to be an important mechanism in regulating RNAP II activity in vivo, and changes in the phosphorylation state of RNAP II are associated with major changes in the pattern of transcription. For example, serum stimulation of quiescent cells, heat shock, and viral infection all dramatically alter cellular transcription and also result in a change in the phosphorylation state of RNAP II (13Dubois M.F. Bellier S. Seo S.J. Bensaude O. J. Cell. Physiol. 1994; 158: 417-426Google Scholar, 14Dubois M.F. Nguyen V.T. Dahmus M.E. Pages G. Pouyssegar J. Bensaude O. EMBO J. 1994; 13: 4787-4797Google Scholar, 15Rice S.A. Long M.C. Lam V. Spencer C.A. J. Virol. 1994; 68: 988-1001Google Scholar).Many different protein kinases have been characterized that can phosphorylate the CTD in vitro. Two yeast protein kinases, CTK1 and KIN28, have been shown to be important for phosphorylation of RNAP II in vivo. Disruption of the CTK1 gene results in a large decrease in RNAP II phosphorylation in vivo (16Lee J.M. Greenleaf A.L. Gene Expr. 1991; 1: 149-167Google Scholar). The null mutant ctk1 cells, although viable, exhibit slow growth and other phenotypes, but it is not known what role CTK1 has in transcription. The KIN28 kinase is found associated with the general transcription factor IIH, which assembles into the preinitiation complex (17Feaver W.J. Svejstrup J.Q. Henry N.L. Kornberg R.D. Cell. 1994; 79: 1103-1109Google Scholar). The KIN28 gene is essential, and loss of the KIN28 kinase activity results in a dramatic decrease in RNAP II phosphorylation and transcriptional activity (18Valay J.G. Simon M. Dubois M.F. Bensaude O. Facca C. Faye G. J. Mol. Biol. 1995; 249: 535-544Google Scholar).Much less is known about CTD phosphatases. A CTD phosphatase activity has been purified from HeLa cells that is highly specific for RNAP II and dephosphorylates the CTD processively (19Chambers R.S. Dahmus M.E. J. Biol. Chem. 1994; 269: 26243-26248Google Scholar). Two proteins with apparent molecular masses of 205 and 150 kDa copurify with the HeLa CTD phosphatase activity, although it is not clear which contains the catalytic activity. In contrast to CTD kinases, HeLa CTD phosphatase does not use recombinant CTD as a substrate (20Chambers R.S. Wang B.Q. Burton Z.F. Dahmus M.E. J. Biol. Chem. 1995; 270: 14962-14969Google Scholar). Furthermore, CTD phosphatase is competitively inhibited by RNAP IIB, a form of RNAP II that lacks the CTD. These and other results suggested that a docking site exists on RNAP II that CTD phosphatase must first bind before it can gain access to the CTD. HeLa CTD phosphatase is also stimulated 5-fold by TFIIF, and the stimulation can be inhibited by TFIIB. The minimal region of TFIIF sufficient to stimulate CTD phosphatase is the C-terminal 160 amino acids of the RAP74 subunit (20Chambers R.S. Wang B.Q. Burton Z.F. Dahmus M.E. J. Biol. Chem. 1995; 270: 14962-14969Google Scholar).Serine/threonine protein phosphatases have been classified into four families, PP1, PP2A, PP2B, and PP2C, based on biochemical properties and amino acid sequence (21Cohen P. Annu. Rev. Biochem. 1989; 58: 453-508Google Scholar). PP1, PP2A, and PP2B are all inhibited by okadaic acid, although with differing sensitivities. PP2B requires calcium ions for activity, and PP2C requires magnesium ions. HeLa CTD phosphatase has been classified as a type 2C phosphatase based on its requirement for magnesium ions and its resistance to okadaic acid. This report describes the purification and characterization of a type 2C phosphatase from yeast specific for the CTD of RNAP II." @default.
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• W1976425824 title "Purification and Characterization of an RNA Polymerase II Phosphatase from Yeast" @default.
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