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      Human cap methyltransferase (RNMT) N-terminal non-catalytic domain mediates recruitment to transcription initiation sites


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          Gene expression in eukaryotes is dependent on the mRNA methyl cap which mediates mRNA processing and translation initiation. Synthesis of the methyl cap initiates with the addition of 7-methylguanosine to the initiating nucleotide of RNA pol II (polymerase II) transcripts, which occurs predominantly during transcription and in mammals is catalysed by RNGTT (RNA guanylyltransferase and 5′ phosphatase) and RNMT (RNA guanine-7 methyltransferase). RNMT has a methyltransferase domain and an N-terminal domain whose function is unclear; it is conserved in mammals, but not required for cap methyltransferase activity. In the present study we report that the N-terminal domain is necessary and sufficient for RNMT recruitment to transcription initiation sites and that recruitment occurs in a DRB (5,6-dichloro-1-β- D-ribofuranosylbenzimidazole)-dependent manner. The RNMT-activating subunit, RAM (RNMT-activating miniprotein), is also recruited to transcription initiation sites via an interaction with RNMT. The RNMT N-terminal domain is required for transcript expression, translation and cell proliferation.


          The mRNA methyl cap recruits the mediators of processing events and translation initiation. We report that RNMT, the human cap methyltransferase, is recruited to RNA polymerase II via the N-terminal domain and is required for gene expression and cell proliferation.

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          Cap and cap-binding proteins in the control of gene expression.

          The 5' mRNA cap structure is essential for efficient gene expression from yeast to human. It plays a critical role in all aspects of the life cycle of an mRNA molecule. Capping occurs co-transcriptionally on the nascent pre-mRNA as it emerges from the RNA exit channel of RNA polymerase II. The cap structure protects mRNAs from degradation by exonucleases and promotes transcription, polyadenylation, splicing, and nuclear export of mRNA and U-rich, capped snRNAs. In addition, the cap structure is required for the optimal translation of the vast majority of cellular mRNAs, and it also plays a prominent role in the expression of eukaryotic, viral, and parasite mRNAs. Cap-binding proteins specifically bind to the cap structure and mediate its functions in the cell. Two major cellular cap-binding proteins have been described to date: eukaryotic translation initiation factor 4E (eIF4E) in the cytoplasm and nuclear cap binding complex (nCBC), a nuclear complex consisting of a cap-binding subunit cap-binding protein 20 (CBP 20) and an auxiliary protein cap-binding protein 80 (CBP 80). nCBC plays an important role in various aspects of nuclear mRNA metabolism such as pre-mRNA splicing and nuclear export, whereas eIF4E acts primarily as a facilitator of mRNA translation. In this review, we highlight recent findings on the role of the cap structure and cap-binding proteins in the regulation of gene expression. We also describe emerging regulatory pathways that control mRNA capping and cap-binding proteins in the cell. Copyright © 2010 John Wiley & Sons, Ltd.
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            RNA polymerase II pauses and associates with pre-mRNA processing factors at both ends of genes.

            We investigated co-transcriptional recruitment of pre-mRNA processing factors to human genes. Capping factors associate with paused RNA polymerase II (pol II) at the 5' ends of quiescent genes. They also track throughout actively transcribed genes and accumulate with paused polymerase in the 3' flanking region. The 3' processing factors cleavage stimulation factor and cleavage polyadenylation specificity factor are maximally recruited 0.5-1.5 kilobases downstream of poly(A) sites where they coincide with capping factors, Spt5, and Ser2-hyperphosphorylated, paused pol II. 3' end processing factors also localize at transcription start sites, and this early recruitment is enhanced after polymerase arrest with the elongation factor DRB. These results suggest that promoters may help specify recruitment of 3' end processing factors. We propose a dual-pausing model wherein elongation arrests near the transcription start site and in the 3' flank to allow co-transcriptional processing by factors recruited to the pol II ternary complex.
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              Viral and cellular mRNA capping: Past and prospects

              Publisher Summary This chapter focuses on the history of the discovery of cap and an update of research on viral and cellular-messenger RNA (mRNA) capping. Cap structures of the type m7 GpppN(m)pN(m)p are present at the 5′ ends of nearly all eukaryotic cellular and viral mRNAs. A cap is added to cellular mRNA precursors and to the transcripts of viruses that replicate in the nucleus during the initial phases of transcription and before other processing events, including internal N6A methylation, 3′-poly (A) addition, and exon splicing. Despite the variations on the methylation theme, the important biological consequences of a cap structure appear to correlate with the N7-methyl on the 5′-terminal G and the two pyrophosphoryl bonds that connect m7G in a 5′–5′ configuration to the first nucleotide of mRNA. In addition to elucidating the biochemical mechanisms of capping and the downstream effects of this 5′- modification on gene expression, the advent of gene cloning has made available an ever-increasing amount of information on the proteins responsible for producing caps and the functional effects of other cap-related interactions. Genetic approaches have demonstrated the lethal consequences of cap failure in yeasts, and complementation studies have shown the evolutionary functional conservation of capping from unicellular to metazoan organisms.

                Author and article information

                Biochem J
                Biochem. J
                Biochemical Journal
                Portland Press Ltd.
                18 July 2013
                13 September 2013
                1 October 2013
                : 455
                : Pt 1
                : 67-73
                Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
                Author notes
                1To whom correspondence should be addressed (email v.h.cowling@ 123456dundee.ac.uk ).
                © 2013 The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Licence (CC-BY)(http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 13 March 2013
                : 16 July 2013
                : 18 July 2013
                Page count
                Figures: 6, References: 26, Pages: 7
                Research Article

                gene expression,methyl cap,transcription,translation,ctd, c-terminal domain,dmem, dulbecco's modified eagle's medium,drb, 5,6-dichloro-1-β-d-ribofuranosyl benzimidazole,gst, glutathione transferase,ha, haemagglutinin,imec, immortalized mammary epithelial cell,hek, human embryonic kidney,nls, nuclear localization signal,pol ii, polymerase ii,ram, rnmt-activating miniprotein,rngtt, rna guanylyltransferase and 5′ phosphatase,rnmt, rna guanine-7 methyltransferase,tss, transcriptional start site,wt, wild-type


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