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Reconstitution of Human Rrna Gene Transcription in Mouse Cells by A ß 2014. Published by The Company of Biologists Ltd | Journal of Cell Science (2014) 127, 3309–3319 doi:10.1242/jcs.146787 RESEARCH ARTICLE Reconstitution of human rRNA gene transcription in mouse cells by a complete SL1 complex Kensaku Murano1, Mitsuru Okuwaki1, Fumitaka Momose2, Michiko Kumakura1, Shuhei Ueshima1, Robert F. Newbold3 and Kyosuke Nagata1,* ABSTRACT TIF-IA are functionally interchangeable between humans and mice, whereas the SL1/TIF-IB complex must be derived from the An important characteristic of the transcription of a ribosomal RNA same species to support rDNA transcription (Bell et al., 1990; gene (rDNA) mediated by DNA-dependent RNA polymerase (Pol) I Heix and Grummt, 1995; Learned et al., 1985; Mishima et al., is its stringent species specificity. SL1/TIF-IB is a key complex for 1982; Rudloff et al., 1994; Schnapp et al., 1993). The human SL1 species specificity, but its functional complex has not been complex contains the TATA-binding protein (TBP) and three reconstituted. Here, we established a novel and highly sensitive TBP-associated factors known as TAFIA (also known as TAFI48 monitoring system for Pol I transcription to reconstitute the SL1 and TAF1A), TAFIB (also known as TAFI63 and TAF1B) and activity in which a transcript harboring a reporter gene synthesized TAFIC (also known as TAFI110C and TAF1C) (Comai et al., by Pol I is amplified and converted into translatable mRNA by 1992). Among these SL1 components, TBP is interchangeable the influenza virus RNA-dependent RNA polymerase. Using this between humans and mice, indicating that TAFIs are responsible monitoring system, we reconstituted Pol I transcription from the for the promoter selectivity of SL1/TIF-IB (Rudloff et al., 1994). human rDNA promoter in mouse cells by expressing four human UV cross-linking experiments have demonstrated that TAFIA and TATA-binding protein (TBP)-associated factors (TAFIs) in the SL1 TAFIB bind to both the homologous and heterologous promoters, complex. The reconstituted SL1 also re-activated human rDNA suggesting that a binding of SL1/TIF-IB to the heterologous transcription in mouse A9 cells carrying an inactive human promoter precludes a formation of productive initiation chromosome 21 that contains the rDNA cluster. Chimeric SL1 complexes (Rudloff et al., 1994). There are contradictory complexes containing human and mouse TAFIs could be formed, reports about reconstituting SL1/TIF-IB activity in vitro. It has but these complexes were inactive for human rDNA transcription. been reported that the three recombinant human TAFIs and the TBP are necessary and sufficient to reconstitute a We conclude that four human TAFIs are necessary and sufficient to overcome the barrier of species specificity for human rDNA transcriptionally active human SL1 complex (Zomerdijk et al., transcription in mouse cells. 1994). In contrast, three mouse recombinant TAFIs and the TBP complex did not reconstitute the TIF-IB activity in an in vitro KEY WORDS: Ribosomal RNA gene, Transcription, Species transcription system (Heix et al., 1997). Later, a further TAFI, specificity, RNA polymerase I, SL1, TIF-IB TAFID (also known as TAFI41 and TAF1D), was identified from the TBP-antibody affinity-purified SL1 fraction (Gorski et al., INTRODUCTION 2007). TAFID co-migrates with TBP on SDS-PAGE, so it One of the most important rDNA transcription issues to be remained unidentified for more than 10 years following the initial addressed is the molecular mechanism of its stringent species identification of the SL1 complex (Comai et al., 1992). TAFIDis specificity (Heix and Grummt, 1995). Three decades ago, involved in rDNA transcription in vivo (Gorski et al., 2007). Grummt et al. demonstrated that in vitro transcription of human Thus, we hypothesize that TAFID is a final component in and mouse rDNAs requires completely homologous extracts reconstituting the human SL1 activity in mouse cells and (Grummt, 1981; Grummt et al., 1982), i.e. human rDNA is not overcoming the rDNA transcription species barrier. transcribed in mouse cell extracts and vice versa. This distinct To examine this hypothesis, we established a novel and highly promoter recognition specificity of Pol I is mediated by a multi- sensitive monitoring system for Pol I transcription. The products subunit factor called SL1 in humans and TIF-IB in mice. SL1/ synthesized by Pol I are not translated to proteins. We tried to TIF-IB recruits Pol I on the rDNA promoter through RRN3/TIF- overcome this problem using the influenza virus RNA-dependent IA and stabilizes the binding of the upstream binding factor RNA polymerases (RdR Pol). Influenza A virus belongs to (UBF) at the rDNA promoter (Friedrich et al., 2005; Moss and the Orthomyxoviridae family, and its genome comprises eight Stefanovsky, 2002; Russell and Zomerdijk, 2006). Pol I, UBF and single-stranded RNAs of negative polarity (Naito et al., 2007). The viral RNA (vRNA) is associated with the viral RdR Pol, 1Department of Infection Biology, Faculty of Medicine and Graduate School of comprising PB1, PB2 and PA subunits, and nucleoprotein (NP), Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, forming viral ribonucleoprotein (vRNP) complexes (Nagata et al., Tsukuba, Ibaraki 305-8575, Japan. 2Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. 3Institute of Cancer 2008; Portela and Digard, 2002). The transcription promoter and Genetics and Pharmacogenomics, Division of Biosciences, School of Health the replication signal of the viral genome exist at the 39 and 59 Sciences and Social Care, Brunel University, Uxbridge, Middlesex UB8 3PH, UK. untranslated terminal regions (UTRs) of each segment. *Author for correspondence ([email protected]) Transcription of the influenza virus genome is initiated by the cap snatching mechanism (Li et al., 2001). The viral RdR Pol Received 21 November 2013; Accepted 25 May 2014 polyadenylates the nascent RNA chain, possibly by a slippage Journal of Cell Science 3309 RESEARCH ARTICLE Journal of Cell Science (2014) 127, 3309–3319 doi:10.1242/jcs.146787 mechanism at the adenylation signal which consists of five to the human rDNA promoter in a reporter plasmid but also seven uracil residues located near the 59 terminal of vRNA (Poon reactivated human rDNA in mouse cells containing the human et al., 1999). Thus, the synthesized RNA has the authentic chromosome 21 carrying an inactive human rDNA cluster. These eukaryotic mRNA structure. An influenza-virus-like particle results indicate that four TAFIs in human SL1 are necessary generation system was established based on the transfection of and sufficient to reconstitute a transcriptionally active SL1 and plasmid DNAs containing the viral genes under the control of the overcome the barrier of species specificity during rDNA Pol I promoter and terminator (Neumann et al., 1999; Zobel et al., transcription in mouse cells. 1993). In this system, an influenza virus genome RNA of an exact size and orientation is synthesized by cellular Pol I. When the RESULTS viral coding region is replaced with a reporter gene (see Fig. 1A), A novel reporter assay system for transcription by Pol I the reporter gene is expressed through the viral system described We developed a novel and sensitive reporter assay system to above. We examined the mechanism of rDNA transcription. In monitor transcription by Pol I in order to precisely analyze the particular, we evaluated its species-specific property using this species barrier for rDNA transcription (Fig. 1A) by modifying the novel and highly sensitive assay system, as we considered the original method (Zobel et al., 1993) for the influenza-virus-like possibility that the species-specificity contradiction might be particle generation system. In this system, engineered vRNA caused by reconstituted Pol I with an activity less than the containing a firefly luciferase (Luc) gene or an EGFP gene detectable level of conventional assay systems. sandwiched between 59- and 39-terminal cis-acting regulatory In the present study, we established a viral RdR Pol-based regions is synthesized by Pol I under the control of the promoter reporter system to monitor Pol I transcription. Using this and terminator in transfected cells. PA, PB1, PB2 and NP are monitoring system, we succeeded in reconstituting Pol I supplied from expression vectors under the control of the Pol transcription from human rDNA in mouse cells by exogenously II promoter (Neumann et al., 1999). mRNA encoding Luc is expressing human TAFIA, B, C and D in the SL1 complex, but synthesized by the influenza viral RdR Pol using RNA not with human TAFIA, TAFIB and TAFIC. Exogenous transcribed by Pol I as a template and the cellular cap structure expression of four TAFIs not only induced transcription from as a primer (Li et al., 2001; Poon et al., 1999). The synthesized Fig. 1. An RdR Pol-based reporter assay system for the transcription by Pol I. (A) A schematic representation of the influenza virus RNA-dependent RNA polymerase (RdR Pol)-mediated Pol I reporter assay system. The influenza virus model RNA genomes are expressed from phPolI-vNS-Luc or phPolI-vNA- EGFP (denoted ‘Luc. or EGFP’) by Pol I. The influenza virus RdR Pol amplifies the synthesized RNA and transcribes mRNA from the model viral RNA of negative polarity. (B) Dependency of the Pol I reporter assay system on viral polymerases and NP. The Luc activity was normalized to the Renilla luciferase activity expressed under the control of the SV40 promoter, a typical Pol II promoter. AU, arbitrary units. Results are mean6s.d. obtained from three independent experiments. (C) Evaluation of Pol I reporter systems. 3 Pol.+NP indicates transfection of plasmids containing RdR Pol components and NP. IRES and PolyA indicate an internal ribosome entry site and a poly(A) signal, respectively. (D) Expression of EGFP in the RdR Pol-based system. HeLa cells were co-transfected with plasmids expressing PA, PB1, PB2 and NP, and phPolI-vNA-EGFP (left panels).
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