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• W1525608001 abstract "Stalled Xenopus RNA polymerase I (pol I) elongation complexes bearing a 52-nucleotide RNA were prepared by promoter-initiated transcription in the absence of UTP. When such complexes were isolated and incubated in the presence of Mg2+, the associated RNA was shortened from the 3′-end, and mono- and dinucleotides were released. Shortened transcripts were still associated with the DNA and were quantitatively reelongated upon addition of NTPs. The cleavage activity could be removed from the pol I-ternary complex with buffers containing 0.25% Sarkosyl. These findings indicate that a factor with characteristics similar to elongation factor TFIIS is associated with the pol I elongation complex. However, addition of recombinant Xenopus TFIIS to Sarkosyl-washed pol I elongation complexes had no effect, whereas it showed the expected effects in control reactions with identically prepared pol II elongation complexes. The results thus suggest the existence of a pol I-specific cleavage/elongation factor. I also report the sequence of a novel type of Xenopus TFIIS. The predicted amino acid sequences of the present and previously identified Xenopus TFIIS are less than 65% conserved. Thus, like mammalian species, Xenopus has at least two highly divergent forms of TFIIS. Stalled Xenopus RNA polymerase I (pol I) elongation complexes bearing a 52-nucleotide RNA were prepared by promoter-initiated transcription in the absence of UTP. When such complexes were isolated and incubated in the presence of Mg2+, the associated RNA was shortened from the 3′-end, and mono- and dinucleotides were released. Shortened transcripts were still associated with the DNA and were quantitatively reelongated upon addition of NTPs. The cleavage activity could be removed from the pol I-ternary complex with buffers containing 0.25% Sarkosyl. These findings indicate that a factor with characteristics similar to elongation factor TFIIS is associated with the pol I elongation complex. However, addition of recombinant Xenopus TFIIS to Sarkosyl-washed pol I elongation complexes had no effect, whereas it showed the expected effects in control reactions with identically prepared pol II elongation complexes. The results thus suggest the existence of a pol I-specific cleavage/elongation factor. I also report the sequence of a novel type of Xenopus TFIIS. The predicted amino acid sequences of the present and previously identified Xenopus TFIIS are less than 65% conserved. Thus, like mammalian species, Xenopus has at least two highly divergent forms of TFIIS. INTRODUCTIONThe process of transcribing a gene can be divided into three main functional steps: initiation, elongation, and termination of transcription. For the eukaryotic ribosomal genes, transcribed by RNA polymerase I (pol I), 1The abbreviations used are: polRNA polymerasebpbase pair(s)ntnucleotide(s) the cis-acting DNA elements comprising the promoter and the terminator have been identified for several species from yeast to man, and trans-acting protein factors required for transcription initiation and termination have been purified and in many cases molecularly cloned (1Reeder R.H. Transcriptional Regulation. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1992: 315-347Google Scholar, 2Jacob S.T. Biochem. J. 1995; 306: 617-626Google Scholar, 3Moss T. Stefanovsky V.Y. Prog. Nucleic Acid Res. Mol. Biol. 1995; 50: 25-66Google Scholar, 4Reeder R.H. Lang W. Mol. Microbiol. 1994; 12: 11-15Google Scholar, 5Evers R. Grummt I. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5827-5831Google Scholar). On the other hand, relatively little is known about the process of transcription elongation by pol I. Due to the considerable length of the ribosomal genes and in light of the finding that at least some pol I even transcribe through the entire intergenic spacer (6Labhart P. Reeder R.H. Cell. 1986; 45: 431-443Google Scholar), elongation of pol I transcription is likely to be an important process and can be expected to be regulated as well. Indeed, a previous study with Xenopus oocytes provided evidence that there are two types of ribosomal gene transcription, which differ in their elongation characteristics (7Labhart P. Gene Expr. 1992; 2: 409-423Google Scholar). The only pol I elongation factor identified to date is TIF-IC, a mouse pol I transcription factor that is involved in both initiation and elongation (8Schnapp G. Schnapp A. Rosenbauer H. Grummt I. EMBO J. 1994; 13: 4028-4035Google Scholar).Much more is known about transcription elongation by pol II, and several protein factors affecting different steps of the elongation process have been identified. TFIIF and SIII, for example, stimulate the rate of elongation (9Bengal E. Flores O. Krauskopf A. Reinberg D. Aloni Y. Mol. Cell. Biol. 1991; 11: 1195-1206Google Scholar, 10Bradsher J.N. Tan S. McLaury H.-J. Conaway J.W. Conaway R.C. J. Biol. Chem. 1993; 268: 25594-25603Google Scholar), whereas TFIIS (SII) promotes read-through of pol II at arrest or pause sites on the template (11Reines D. Chamberlin M.J. Kane C.M. J. Biol. Chem. 1989; 264: 10799-10809Google Scholar). Others, like TFIIH and TFIIE, are required for promoter escape, an early step in elongation (12Goodrich J.A. Tjian R. Cell. 1994; 77: 145-156Google Scholar). The present study is concerned with TFIIS and TFIIS-like factors. cDNAs encoding TFIIS have been isolated from various species, including Xenopus (Refs. 13Kugawa F. Shinga J. Imagawa M. Arae K. Nagano M. Shibata M. Shiokawa K. Aoki M. Biochem. Biophys. Res. Commun. 1996; 222: 541-546Google Scholar and 14Plant K.E. Hair A. Morgan G.T. Nucleic Acids Res. 1996; 24: 3514-3521Google Scholar, and this study). TFIIS binds to pol II in the elongation complex and activates an intrinsic RNase activity that shortens the nascent transcript from the 3′-end (15Reines D. J. Biol. Chem. 1992; 267: 3795-3800Google Scholar, 16Izban M.G. Luse D.S. Genes Dev. 1992; 6: 1342-1356Google Scholar) (reviewed in 17Kassavetic G.A. Geiduschek E.P. Science. 1993; 259: 944-945Google Scholar). The transcript cleavage is a hydrolytic reaction and liberates mono- and/or short oligonucleotides depending on the conformation and location of the paused elongation complex (18Izban M.G. Luse D.S. J. Biol. Chem. 1993; 268: 12874-12885Google Scholar, 19Gu W. Reines D. J. Biol. Chem. 1995; 270: 30441-30447Google Scholar). The shortened transcript can be reextended in the presence of NTPs indicating that the 3′-ends of the shortened transcripts are still associated with the catalytic site of pol II. It is thought that RNA cleavage is important for the observed activation of read-through by TFIIS possibly by allowing the arrested elongation complex to make several attempts to overcome an obstacle. Whether these in vitro observations reflect the in vivo role of TFIIS is an unresolved question. In yeast, TFIIS is not essential for viability, but cells lacking TFIIS are sensitive toward 6-azauracil (20Nakanishi T. Shimoaraiso M. Kubo T. Natori S. J. Biol. Chem. 1995; 270: 8991-8995Google Scholar, 21Nakanishi T. Nakano A. Nomura K. Sekimizu K. Natori S. J. Biol. Chem. 1992; 267: 13200-13204Google Scholar).TFIIS is generally considered to be specific for pol II. Thus, TFIIS purified from mouse cells did not affect pol I in nonspecific transcription assays (22Sekimizu K. Kobayashi N. Mizuno D. Natori S. Biochemistry. 1976; 15: 5064-5070Google Scholar), and in a different study TFIIS was found to bind to pol II but not to pol III (23Reinberg D. Roeder R.G. J. Biol. Chem. 1987; 262: 3331-3337Google Scholar). However, another early paper reported that partially purified yeast TFIIS stimulated both pol I and pol II (24Sawadogo M. Lescure B. Sentenac A. Fromageot P. Biochemistry. 1981; 20: 3542-3547Google Scholar). The question of the pol specificity of TFIIS has not been reinvestigated by looking at the more defined effects of TFIIS on paused elongation complexes. In search of pol I-specific elongation factors, I tested whether evidence for an involvement of TFIIS or a TFIIS-like factor in transcription by pol I could be obtained. I used the cleavage of nascent transcripts in a stalled pol I elongation complex as an assay for such a factor. My results show that there is indeed an activity associated with pol I ternary complexes that has similar functional characteristics as TFIIS but is distinct from TFIIS.DISCUSSIONTFIIS is a transcription factor that was originally identified as an activity that stimulates nonspecific transcription by purified pol II (34Natori S. Takeuchi K. Takahashi K. Mizuno D. J. Biochem. (Tokyo). 1973; 73: 879-888Google Scholar). It was later classified as an elongation factor because it suppresses pausing and increases the yield of long transcripts in specific transcription reactions (23Reinberg D. Roeder R.G. J. Biol. Chem. 1987; 262: 3331-3337Google Scholar, 35Rappaport J. Reinberg D. Zandomeni R. Weinmann R. J. Biol. Chem. 1987; 262: 5227-5232Google Scholar). TFIIS exerts its function in elongation by helping stalled or arrested pol II to read through various transcriptional blockages (11Reines D. Chamberlin M.J. Kane C.M. J. Biol. Chem. 1989; 264: 10799-10809Google Scholar, 36Christie K.R. Awrey D.E. Edwards A.M. Kane C.M. J. Biol. Chem. 1994; 269: 936-943Google Scholar, 37Reines D. Mote Jr., J. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 1917-1921Google Scholar). In stalled and arrested elongation complexes, TFIIS stimulates the cleavage of the nascent transcripts at the 3′-end and a concomitant backward movement of the catalytic site of pol II (15Reines D. J. Biol. Chem. 1992; 267: 3795-3800Google Scholar, 16Izban M.G. Luse D.S. Genes Dev. 1992; 6: 1342-1356Google Scholar). This cleavage reaction is thought to be important or even required for efficient read-through at these arrest sites.It is reasonable to postulate that the transcription of ribosomal genes also requires an elongation factor. As discussed in the Introduction, the available data appeared insufficient to fully rule out that TFIIS itself would also serve as an elongation factor for pol I. The stimulation of the pol-associated transcript cleavage activity is a more diagnostic assay for TFIIS than the stimulation of nonspecific transcription. I therefore investigated whether TFIIS would stimulate the cleavage of nascent transcripts in a stalled pol I elongation complex. My data show that recombinant Xenopus TFIIS, when added to Sarkosyl-washed pol I elongation complexes that stalled after transcription of a 52-nt RNA, did not stimulate cleavage of this transcript. This negative result was substantiated by control experiments with Sarkosyl-washed pol II elongation complexes, where the expected effects of Xenopus TFIIS were readily detected. Furthermore, Xenopus TFIIS showed all the known characteristics in these pol II controls, like Mg2+ dependence, α-amanitin sensitivity, and dependence on the zinc ribbon domain near its C terminus.Whereas the present results make an involvement of TFIIS in pol I transcription very unlikely, they also show that a different activity that is similar to TFIIS is present in the pol I elongation complex. Like TFIIS, this activity shortens the nascent RNA from the 3′-end releasing mono- and dinucleotides. The shortened transcripts are still associated with the catalytic site of pol I, since they are readily reextended upon addition of the appropriate NTPs. Finally, the cleavage activity is removed from the pol I elongation complex with 0.1-0.25% Sarkosyl; the same conditions also remove TFIIS from the pol II elongation complex (38Wiest D.K. Wang D. Hawley D.K. J. Biol. Chem. 1992; 267: 7733-7744Google Scholar). Unlike the TFIIS-induced RNA cleavage reaction in pol II ternary complexes, the pol I-associated cleavage reaction is resistant to high concentrations of α-amanitin, a finding that is consistent with an involvement of the catalytic site of pol I in the transcript shortening.In stalled or arrested pol II elongation complexes a low level of RNA cleavage is taking place even in the absence of an auxiliary factor like TFIIS, indicating that the nucleolytic activity resides in pol II (15Reines D. J. Biol. Chem. 1992; 267: 3795-3800Google Scholar, 16Izban M.G. Luse D.S. Genes Dev. 1992; 6: 1342-1356Google Scholar, 17Kassavetic G.A. Geiduschek E.P. Science. 1993; 259: 944-945Google Scholar, 39Wang D. Hawley D.K. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 843-847Google Scholar). For pol III this type of hydrolytic cleavage is the only type that has been observed so far, and a TFIIS-like, dissociable activity like the one described in this study has not been identified in pol III complexes (30Whitehall S.K. Bardeleben C. Kassavetis G.A. J. Biol. Chem. 1994; 269: 2299-2306Google Scholar). In the present experiments I did not detect an intrinsic activity of pol I that would be active without an auxiliary factor. It can be expected, however, that pol I by itself would also show some nucleolytic activity if the sensitivity of the assay was increased. In any case, it is clear that for both pol II and pol I, TFIIS or a TFIIS-like factor is required for efficient transcript cleavage.After submission of the original version of this manuscript, the identification of a yeast activity that shortens nascent pol I transcripts from the 3′-end was reported (40Tschochner H. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 12914-12919Google Scholar). Whereas this yeast factor and the present Xenopus activity clearly seem to be related, the available data are insufficient to decide whether they represent homologous protein factors. It will be interesting to determine the Mg2+ requirement and the Sarkosyl sensitivity of the yeast factor as well as the size of the liberated cleavage products. Apparent differences lie in the chromatographic behavior and in the finding that the yeast activity can be detected even in the presence of nucleotides.Sequences encoding Xenopus TFIIS were recently reported by Kugawa et al. (13Kugawa F. Shinga J. Imagawa M. Arae K. Nagano M. Shibata M. Shiokawa K. Aoki M. Biochem. Biophys. Res. Commun. 1996; 222: 541-546Google Scholar) and Plant et al. (14Plant K.E. Hair A. Morgan G.T. Nucleic Acids Res. 1996; 24: 3514-3521Google Scholar). The latter paper identified two genes for Xenopus TFIIS, termed xTFIIS.oA and xTFIIS.oB, which were interpreted to represent the two gene copies present in the two homologous genomes of the tetraploid Xenopus laevis The two predicted proteins are 91% identical. The deduced protein sequence reported by Kugawa et al. (13Kugawa F. Shinga J. Imagawa M. Arae K. Nagano M. Shibata M. Shiokawa K. Aoki M. Biochem. Biophys. Res. Commun. 1996; 222: 541-546Google Scholar) is 100% identical to xTFIIS.oA Interestingly, the sequence of the cDNA isolated for the present study, which I will refer to as xTFIIS.l, is very different from both xTFIIS.oA and xTFIIS.oB (Fig. 6). The predicted xTFIIS.l and xTFIIS.oA/B proteins are only 68-70% identical in the 82-amino acid long N-terminal domain and 72-74% identical in the 175-amino acid C-terminal domain. The regions between these two domains are not conserved and of different lengths (46 versus 35 amino acids). The similarity between these two Xenopus proteins is thus about the same as between TFIIS from different vertebrate species. Using reverse transcription-polymerase chain reaction, I found that mRNAs encoding xTFIIS.oA/B and xTFIIS.l are both expressed in a Xenopus tissue culture cell line. 2P. Labhart, unpublished results. Xenopus thus has two highly divergent forms of TFIIS, which do not appear to reflect the duplication of its genome during evolution. This finding has a precedent in mammalian species, where in addition to the general form of TFIIS a testis-specific type was identified (41Xu Q. Nakanishi T. Sekimizu K. Natori S. J. Biol. Chem. 1994; 269: 3100-3103Google Scholar, 42Umehara T. Kida S. Yamamoto T. Horikoshi M. Gene (Amst.). 1995; 167: 297-302Google Scholar).It will be interesting to see whether the present TFIIS-like factor belongs to the TFIIS family of proteins. In addition, it will be important to investigate whether and how it changes the properties of the pol I elongation complex. The experiment shown in Fig. 2 shows that in the presence of NTPs a pol I elongation complex is able to elongate to the end of the template regardless of whether it contains this factor (lanes 4 and 11). Furthermore, on the template that was used no intrinsic arrest or pause sites were uncovered during elongation of Sarkosyl-washed complexes. The purification and cloning of this factor will be necessary to investigate its role, if any, in transcription elongation by pol I. INTRODUCTIONThe process of transcribing a gene can be divided into three main functional steps: initiation, elongation, and termination of transcription. For the eukaryotic ribosomal genes, transcribed by RNA polymerase I (pol I), 1The abbreviations used are: polRNA polymerasebpbase pair(s)ntnucleotide(s) the cis-acting DNA elements comprising the promoter and the terminator have been identified for several species from yeast to man, and trans-acting protein factors required for transcription initiation and termination have been purified and in many cases molecularly cloned (1Reeder R.H. Transcriptional Regulation. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1992: 315-347Google Scholar, 2Jacob S.T. Biochem. J. 1995; 306: 617-626Google Scholar, 3Moss T. Stefanovsky V.Y. Prog. Nucleic Acid Res. Mol. Biol. 1995; 50: 25-66Google Scholar, 4Reeder R.H. Lang W. Mol. Microbiol. 1994; 12: 11-15Google Scholar, 5Evers R. Grummt I. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5827-5831Google Scholar). On the other hand, relatively little is known about the process of transcription elongation by pol I. Due to the considerable length of the ribosomal genes and in light of the finding that at least some pol I even transcribe through the entire intergenic spacer (6Labhart P. Reeder R.H. Cell. 1986; 45: 431-443Google Scholar), elongation of pol I transcription is likely to be an important process and can be expected to be regulated as well. Indeed, a previous study with Xenopus oocytes provided evidence that there are two types of ribosomal gene transcription, which differ in their elongation characteristics (7Labhart P. Gene Expr. 1992; 2: 409-423Google Scholar). The only pol I elongation factor identified to date is TIF-IC, a mouse pol I transcription factor that is involved in both initiation and elongation (8Schnapp G. Schnapp A. Rosenbauer H. Grummt I. EMBO J. 1994; 13: 4028-4035Google Scholar).Much more is known about transcription elongation by pol II, and several protein factors affecting different steps of the elongation process have been identified. TFIIF and SIII, for example, stimulate the rate of elongation (9Bengal E. Flores O. Krauskopf A. Reinberg D. Aloni Y. Mol. Cell. Biol. 1991; 11: 1195-1206Google Scholar, 10Bradsher J.N. Tan S. McLaury H.-J. Conaway J.W. Conaway R.C. J. Biol. Chem. 1993; 268: 25594-25603Google Scholar), whereas TFIIS (SII) promotes read-through of pol II at arrest or pause sites on the template (11Reines D. Chamberlin M.J. Kane C.M. J. Biol. Chem. 1989; 264: 10799-10809Google Scholar). Others, like TFIIH and TFIIE, are required for promoter escape, an early step in elongation (12Goodrich J.A. Tjian R. Cell. 1994; 77: 145-156Google Scholar). The present study is concerned with TFIIS and TFIIS-like factors. cDNAs encoding TFIIS have been isolated from various species, including Xenopus (Refs. 13Kugawa F. Shinga J. Imagawa M. Arae K. Nagano M. Shibata M. Shiokawa K. Aoki M. Biochem. Biophys. Res. Commun. 1996; 222: 541-546Google Scholar and 14Plant K.E. Hair A. Morgan G.T. Nucleic Acids Res. 1996; 24: 3514-3521Google Scholar, and this study). TFIIS binds to pol II in the elongation complex and activates an intrinsic RNase activity that shortens the nascent transcript from the 3′-end (15Reines D. J. Biol. Chem. 1992; 267: 3795-3800Google Scholar, 16Izban M.G. Luse D.S. Genes Dev. 1992; 6: 1342-1356Google Scholar) (reviewed in 17Kassavetic G.A. Geiduschek E.P. Science. 1993; 259: 944-945Google Scholar). The transcript cleavage is a hydrolytic reaction and liberates mono- and/or short oligonucleotides depending on the conformation and location of the paused elongation complex (18Izban M.G. Luse D.S. J. Biol. Chem. 1993; 268: 12874-12885Google Scholar, 19Gu W. Reines D. J. Biol. Chem. 1995; 270: 30441-30447Google Scholar). The shortened transcript can be reextended in the presence of NTPs indicating that the 3′-ends of the shortened transcripts are still associated with the catalytic site of pol II. It is thought that RNA cleavage is important for the observed activation of read-through by TFIIS possibly by allowing the arrested elongation complex to make several attempts to overcome an obstacle. Whether these in vitro observations reflect the in vivo role of TFIIS is an unresolved question. In yeast, TFIIS is not essential for viability, but cells lacking TFIIS are sensitive toward 6-azauracil (20Nakanishi T. Shimoaraiso M. Kubo T. Natori S. J. Biol. Chem. 1995; 270: 8991-8995Google Scholar, 21Nakanishi T. Nakano A. Nomura K. Sekimizu K. Natori S. J. Biol. Chem. 1992; 267: 13200-13204Google Scholar).TFIIS is generally considered to be specific for pol II. Thus, TFIIS purified from mouse cells did not affect pol I in nonspecific transcription assays (22Sekimizu K. Kobayashi N. Mizuno D. Natori S. Biochemistry. 1976; 15: 5064-5070Google Scholar), and in a different study TFIIS was found to bind to pol II but not to pol III (23Reinberg D. Roeder R.G. J. Biol. Chem. 1987; 262: 3331-3337Google Scholar). However, another early paper reported that partially purified yeast TFIIS stimulated both pol I and pol II (24Sawadogo M. Lescure B. Sentenac A. Fromageot P. Biochemistry. 1981; 20: 3542-3547Google Scholar). The question of the pol specificity of TFIIS has not been reinvestigated by looking at the more defined effects of TFIIS on paused elongation complexes. In search of pol I-specific elongation factors, I tested whether evidence for an involvement of TFIIS or a TFIIS-like factor in transcription by pol I could be obtained. I used the cleavage of nascent transcripts in a stalled pol I elongation complex as an assay for such a factor. My results show that there is indeed an activity associated with pol I ternary complexes that has similar functional characteristics as TFIIS but is distinct from TFIIS." @default.
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• W1525608001 title "Transcript Cleavage in an RNA Polymerase I Elongation Complex" @default.
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