Telomerase downregulation induced by the G‐quadruplex ligand 12459 in A549 cells is mediated by hTERT RNA alternative splicing
Identifieur interne : 002418 ( Istex/Corpus ); précédent : 002417; suivant : 002419Telomerase downregulation induced by the G‐quadruplex ligand 12459 in A549 cells is mediated by hTERT RNA alternative splicing
Auteurs : Dennis Gomez ; Thibault Lemarteleur ; Laurent Lacroix ; Patrick Mailliet ; Jean-Louis Mergny ; Jean-Franc Ois RiouSource :
- Nucleic Acids Research [ 0305-1048 ] ; 2004-01-16.
Abstract
Ligand 12459, a potent G‐quadruplex‐interacting agent that belongs to the triazine series, was previously shown to downregulate telomerase activity in the human A549 lung carcinoma cell line. We show here that the downregulation of telomerase activity is caused by an alteration of the hTERT splicing pattern induced by 12459, i.e. an almost complete disappearance of the active (+α,+β) transcript and an over‐expression of the inactive –β transcript. Spliced intron 6 forming the –β hTERT transcript contained several tracks of G‐rich sequences able to form G‐quadruplexes. By using a specific PCR‐stop assay, we show that 12459 is able to stabilize the formation of these G‐quadruplex structures. A549 cell line clones selected for resistance to 12459 have been analyzed for their hTERT splicing pattern. Resistant clones are able to maintain the active hTERT transcript under 12459 treatment, suggesting the appearance of mechanisms able to bypass the 12459‐induced splicing alterations. In contrast to 12459, telomestatin and BRACO19, two other G‐quadruplex‐interacting agents, have no effect on the hTERT splicing pattern in A549 cells, are cytotoxic against the A549‐resistant clones and display a lower efficiency to stabilize hTERT G‐quadruplexes. These results lead us to propose that 12459 impairs the splicing machinery of hTERT through stabilization of quadruplexes located in the hTERT intron 6. Differences of selectivity between 12459, BRACO19 and telomestatin for these hTERT quadruplexes may be important to explain their respective activity and inactivity against hTERT splicing.
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DOI: 10.1093/nar/gkh181
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Acids Res.</title><idno type="ISSN">0305-1048</idno><idno type="eISSN">1362-4962</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2004-01-16">2004-01-16</date><biblScope unit="volume">32</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="371">371</biblScope><biblScope unit="page" to="379">379</biblScope></imprint><idno type="ISSN">0305-1048</idno></series><idno type="istex">F134CD436FA349076D092FA4F3E7F67E28481FBE</idno><idno type="DOI">10.1093/nar/gkh181</idno><idno type="local">gkh181</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0305-1048</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Ligand 12459, a potent G‐quadruplex‐interacting agent that belongs to the triazine series, was previously shown to downregulate telomerase activity in the human A549 lung carcinoma cell line. We show here that the downregulation of telomerase activity is caused by an alteration of the hTERT splicing pattern induced by 12459, i.e. an almost complete disappearance of the active (+α,+β) transcript and an over‐expression of the inactive –β transcript. Spliced intron 6 forming the –β hTERT transcript contained several tracks of G‐rich sequences able to form G‐quadruplexes. By using a specific PCR‐stop assay, we show that 12459 is able to stabilize the formation of these G‐quadruplex structures. A549 cell line clones selected for resistance to 12459 have been analyzed for their hTERT splicing pattern. Resistant clones are able to maintain the active hTERT transcript under 12459 treatment, suggesting the appearance of mechanisms able to bypass the 12459‐induced splicing alterations. In contrast to 12459, telomestatin and BRACO19, two other G‐quadruplex‐interacting agents, have no effect on the hTERT splicing pattern in A549 cells, are cytotoxic against the A549‐resistant clones and display a lower efficiency to stabilize hTERT G‐quadruplexes. These results lead us to propose that 12459 impairs the splicing machinery of hTERT through stabilization of quadruplexes located in the hTERT intron 6. Differences of selectivity between 12459, BRACO19 and telomestatin for these hTERT quadruplexes may be important to explain their respective activity and inactivity against hTERT splicing.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Dennis Gomez</name><affiliations><json:string>Onco‐Pharmacologie and</json:string></affiliations></json:item><json:item><name>Thibault Lemarteleur</name><affiliations><json:string>Onco‐Pharmacologie and</json:string><json:string>EA3306, IFR53, UFR de Pharmacie, Université de Reims Champagne‐Ardenne, 51096 Reims, France,</json:string></affiliations></json:item><json:item><name>Laurent Lacroix</name><affiliations><json:string>Laboratoire de Biophysique, INSERM U565, CNRS UMR 5153, Muséum National d’Histoire Naturelle USM 0503, 75005, Paris, France and</json:string></affiliations></json:item><json:item><name>Patrick Mailliet</name><affiliations><json:string>Aventis Pharma SA, Centre de Recherche de Paris, 94403, Vitry sur Seine, France</json:string></affiliations></json:item><json:item><name>Jean‐Louis Mergny</name><affiliations><json:string>Laboratoire de Biophysique, INSERM U565, CNRS UMR 5153, Muséum National d’Histoire Naturelle USM 0503, 75005, Paris, France and</json:string></affiliations></json:item><json:item><name>Jean‐François Riou</name><affiliations><json:string>Onco‐Pharmacologie and</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>4</value></json:item></subject><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Ligand 12459, a potent G‐quadruplex‐interacting agent that belongs to the triazine series, was previously shown to downregulate telomerase activity in the human A549 lung carcinoma cell line. We show here that the downregulation of telomerase activity is caused by an alteration of the hTERT splicing pattern induced by 12459, i.e. an almost complete disappearance of the active (+α,+β) transcript and an over‐expression of the inactive –β transcript. Spliced intron 6 forming the –β hTERT transcript contained several tracks of G‐rich sequences able to form G‐quadruplexes. By using a specific PCR‐stop assay, we show that 12459 is able to stabilize the formation of these G‐quadruplex structures. A549 cell line clones selected for resistance to 12459 have been analyzed for their hTERT splicing pattern. Resistant clones are able to maintain the active hTERT transcript under 12459 treatment, suggesting the appearance of mechanisms able to bypass the 12459‐induced splicing alterations. In contrast to 12459, telomestatin and BRACO19, two other G‐quadruplex‐interacting agents, have no effect on the hTERT splicing pattern in A549 cells, are cytotoxic against the A549‐resistant clones and display a lower efficiency to stabilize hTERT G‐quadruplexes. These results lead us to propose that 12459 impairs the splicing machinery of hTERT through stabilization of quadruplexes located in the hTERT intron 6. Differences of selectivity between 12459, BRACO19 and telomestatin for these hTERT quadruplexes may be important to explain their respective activity and inactivity against hTERT splicing.</abstract><qualityIndicators><score>9.796</score><pdfVersion>1.2</pdfVersion><pdfPageSize>611 x 791 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>1</keywordCount><abstractCharCount>1597</abstractCharCount><pdfWordCount>5529</pdfWordCount><pdfCharCount>36187</pdfCharCount><pdfPageCount>9</pdfPageCount><abstractWordCount>233</abstractWordCount></qualityIndicators><title>Telomerase downregulation induced by the G‐quadruplex ligand 12459 in A549 cells is mediated by hTERT RNA alternative splicing</title><refBibs><json:item><author><json:item><name>M,J Mceachern</name></json:item><json:item><name>A Krauskopf</name></json:item><json:item><name>E,H Blackburn</name></json:item></author><host><volume>34</volume><pages><last>358</last><first>331</first></pages><author></author><title>Annu. 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Tel: +33 326 91 80 13; Fax: +33 326 91 37 30; Email: jf.riou@univ‐reims.fr</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Telomerase downregulation induced by the G‐quadruplex ligand 12459 in A549 cells is mediated by hTERT RNA alternative splicing</title><author xml:id="author-1"><persName><forename type="first">Dennis</forename><surname>Gomez</surname></persName><affiliation>Onco‐Pharmacologie and</affiliation></author><author xml:id="author-2"><persName><forename type="first">Thibault</forename><surname>Lemarteleur</surname></persName><affiliation>Onco‐Pharmacologie and</affiliation><affiliation>EA3306, IFR53, UFR de Pharmacie, Université de Reims Champagne‐Ardenne, 51096 Reims, France,</affiliation></author><author xml:id="author-3"><persName><forename type="first">Laurent</forename><surname>Lacroix</surname></persName><affiliation>Laboratoire de Biophysique, INSERM U565, CNRS UMR 5153, Muséum National d’Histoire Naturelle USM 0503, 75005, Paris, France and</affiliation></author><author xml:id="author-4"><persName><forename type="first">Patrick</forename><surname>Mailliet</surname></persName><affiliation>Aventis Pharma SA, Centre de Recherche de Paris, 94403, Vitry sur Seine, France</affiliation></author><author xml:id="author-5"><persName><forename type="first">Jean‐Louis</forename><surname>Mergny</surname></persName><affiliation>Laboratoire de Biophysique, INSERM U565, CNRS UMR 5153, Muséum National d’Histoire Naturelle USM 0503, 75005, Paris, France and</affiliation></author><author xml:id="author-6"><persName><forename type="first">Jean‐François</forename><surname>Riou</surname></persName><affiliation>Onco‐Pharmacologie and</affiliation></author></analytic><monogr><title level="j">Nucleic Acids Research</title><title level="j" type="abbrev">Nucl. Acids Res.</title><idno type="pISSN">0305-1048</idno><idno type="eISSN">1362-4962</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2004-01-16"></date><biblScope unit="volume">32</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="371">371</biblScope><biblScope unit="page" to="379">379</biblScope></imprint></monogr><idno type="istex">F134CD436FA349076D092FA4F3E7F67E28481FBE</idno><idno type="DOI">10.1093/nar/gkh181</idno><idno type="local">gkh181</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2004</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Ligand 12459, a potent G‐quadruplex‐interacting agent that belongs to the triazine series, was previously shown to downregulate telomerase activity in the human A549 lung carcinoma cell line. We show here that the downregulation of telomerase activity is caused by an alteration of the hTERT splicing pattern induced by 12459, i.e. an almost complete disappearance of the active (+α,+β) transcript and an over‐expression of the inactive –β transcript. Spliced intron 6 forming the –β hTERT transcript contained several tracks of G‐rich sequences able to form G‐quadruplexes. By using a specific PCR‐stop assay, we show that 12459 is able to stabilize the formation of these G‐quadruplex structures. A549 cell line clones selected for resistance to 12459 have been analyzed for their hTERT splicing pattern. Resistant clones are able to maintain the active hTERT transcript under 12459 treatment, suggesting the appearance of mechanisms able to bypass the 12459‐induced splicing alterations. In contrast to 12459, telomestatin and BRACO19, two other G‐quadruplex‐interacting agents, have no effect on the hTERT splicing pattern in A549 cells, are cytotoxic against the A549‐resistant clones and display a lower efficiency to stabilize hTERT G‐quadruplexes. These results lead us to propose that 12459 impairs the splicing machinery of hTERT through stabilization of quadruplexes located in the hTERT intron 6. Differences of selectivity between 12459, BRACO19 and telomestatin for these hTERT quadruplexes may be important to explain their respective activity and inactivity against hTERT splicing.</p></abstract><textClass><keywords scheme="keyword"><list><head>hwp-journal-coll</head><item><term>4</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2004-01-16">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-12-22">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/F134CD436FA349076D092FA4F3E7F67E28481FBE/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="US-ASCII"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article xml:lang="en" article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">nar</journal-id><journal-id journal-id-type="nlm-ta">Nucleic Acids Res</journal-id><journal-id journal-id-type="publisher-id">nar</journal-id><journal-title>Nucleic Acids Research</journal-title><abbrev-journal-title abbrev-type="publisher">Nucl. Acids Res.</abbrev-journal-title><issn pub-type="ppub">0305-1048</issn><issn pub-type="epub">1362-4962</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="other">gkh181</article-id><article-id pub-id-type="doi">10.1093/nar/gkh181</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group><subj-group subj-group-type="hwp-journal-coll"><subject>4</subject></subj-group></article-categories><title-group><article-title>Telomerase downregulation induced by the G‐quadruplex ligand 12459 in A549 cells is mediated by hTERT RNA alternative splicing</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Gomez</surname><given-names>Dennis</given-names></name><xref rid="GKH181A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Lemarteleur</surname><given-names>Thibault</given-names></name><xref rid="GKH181A1">1</xref><xref rid="GKH181A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Lacroix</surname><given-names>Laurent</given-names></name><xref rid="GKH181A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Mailliet</surname><given-names>Patrick</given-names></name><xref rid="GKH181A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Mergny</surname><given-names>Jean‐Louis</given-names></name><xref rid="GKH181A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Riou</surname><given-names>Jean‐François</given-names></name><xref rid="COR1">*</xref><xref rid="GKH181A1">1</xref></contrib><aff id="GKH181A1"><label>1</label>Onco‐Pharmacologie and</aff><aff id="GKH181A2"><label>2</label>EA3306, IFR53, UFR de Pharmacie, Université de Reims Champagne‐Ardenne, 51096 Reims, France,</aff><aff id="GKH181A3"><label>3</label>Laboratoire de Biophysique, INSERM U565, CNRS UMR 5153, Muséum National d’Histoire Naturelle USM 0503, 75005, Paris, France and</aff><aff id="GKH181A4"><label>4</label>Aventis Pharma SA, Centre de Recherche de Paris, 94403, Vitry sur Seine, France</aff></contrib-group><author-notes><corresp id="COR1">*To whom correspondence should be addressed at UFR de Pharmacie, Université de Reims Champagne‐Ardenne, 51 rue Cognacq‐Jay, 51096 Reims, France. Tel: +33 326 91 80 13; Fax: +33 326 91 37 30; Email: <ext-link xlink:href="jf.riou@univ-reims.fr" ext-link-type="email">jf.riou@univ‐reims.fr</ext-link></corresp></author-notes><pub-date pub-type="ppub"><day>16</day><month>01</month><year>2004</year></pub-date><volume>32</volume><issue>1</issue><fpage>371</fpage><lpage>379</lpage><permissions><copyright-statement>Oxford University Press</copyright-statement><copyright-year>2004</copyright-year></permissions><abstract xml:lang="en"><p>Ligand 12459, a potent G‐quadruplex‐interacting agent that belongs to the triazine series, was previously shown to downregulate telomerase activity in the human A549 lung carcinoma cell line. We show here that the downregulation of telomerase activity is caused by an alteration of the hTERT splicing pattern induced by 12459, i.e. an almost complete disappearance of the active (+α,+β) transcript and an over‐expression of the inactive –β transcript. Spliced intron 6 forming the –β hTERT transcript contained several tracks of G‐rich sequences able to form G‐quadruplexes. By using a specific PCR‐stop assay, we show that 12459 is able to stabilize the formation of these G‐quadruplex structures. A549 cell line clones selected for resistance to 12459 have been analyzed for their hTERT splicing pattern. Resistant clones are able to maintain the active hTERT transcript under 12459 treatment, suggesting the appearance of mechanisms able to bypass the 12459‐induced splicing alterations. In contrast to 12459, telomestatin and BRACO19, two other G‐quadruplex‐interacting agents, have no effect on the hTERT splicing pattern in A549 cells, are cytotoxic against the A549‐resistant clones and display a lower efficiency to stabilize hTERT G‐quadruplexes. These results lead us to propose that 12459 impairs the splicing machinery of hTERT through stabilization of quadruplexes located in the hTERT intron 6. Differences of selectivity between 12459, BRACO19 and telomestatin for these hTERT quadruplexes may be important to explain their respective activity and inactivity against hTERT splicing.</p></abstract><custom-meta-wrap><custom-meta><meta-name>hwp-legacy-fpage</meta-name><meta-value>371</meta-value></custom-meta><custom-meta><meta-name>hwp-legacy-dochead</meta-name><meta-value>Article</meta-value></custom-meta></custom-meta-wrap></article-meta><notes><p content-type="arthw-misc">Received August 23, 2003; Revised November 13, 2003;; Accepted November 26, 2003</p></notes></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Telomerase downregulation induced by the G‐quadruplex ligand 12459 in A549 cells is mediated by hTERT RNA alternative splicing</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Telomerase downregulation induced by the G‐quadruplex ligand 12459 in A549 cells is mediated by hTERT RNA alternative splicing</title></titleInfo><name type="personal"><namePart type="given">Dennis</namePart><namePart type="family">Gomez</namePart><affiliation>Onco‐Pharmacologie and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thibault</namePart><namePart type="family">Lemarteleur</namePart><affiliation>Onco‐Pharmacologie and</affiliation><affiliation>EA3306, IFR53, UFR de Pharmacie, Université de Reims Champagne‐Ardenne, 51096 Reims, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Laurent</namePart><namePart type="family">Lacroix</namePart><affiliation>Laboratoire de Biophysique, INSERM U565, CNRS UMR 5153, Muséum National d’Histoire Naturelle USM 0503, 75005, Paris, France and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Patrick</namePart><namePart type="family">Mailliet</namePart><affiliation>Aventis Pharma SA, Centre de Recherche de Paris, 94403, Vitry sur Seine, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jean‐Louis</namePart><namePart type="family">Mergny</namePart><affiliation>Laboratoire de Biophysique, INSERM U565, CNRS UMR 5153, Muséum National d’Histoire Naturelle USM 0503, 75005, Paris, France and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jean‐François</namePart><namePart type="family">Riou</namePart><affiliation>Onco‐Pharmacologie and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><subject><genre>hwp-journal-coll</genre><topic>4</topic></subject><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2004-01-16</dateIssued><copyrightDate encoding="w3cdtf">2004</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Ligand 12459, a potent G‐quadruplex‐interacting agent that belongs to the triazine series, was previously shown to downregulate telomerase activity in the human A549 lung carcinoma cell line. We show here that the downregulation of telomerase activity is caused by an alteration of the hTERT splicing pattern induced by 12459, i.e. an almost complete disappearance of the active (+α,+β) transcript and an over‐expression of the inactive –β transcript. Spliced intron 6 forming the –β hTERT transcript contained several tracks of G‐rich sequences able to form G‐quadruplexes. By using a specific PCR‐stop assay, we show that 12459 is able to stabilize the formation of these G‐quadruplex structures. A549 cell line clones selected for resistance to 12459 have been analyzed for their hTERT splicing pattern. Resistant clones are able to maintain the active hTERT transcript under 12459 treatment, suggesting the appearance of mechanisms able to bypass the 12459‐induced splicing alterations. In contrast to 12459, telomestatin and BRACO19, two other G‐quadruplex‐interacting agents, have no effect on the hTERT splicing pattern in A549 cells, are cytotoxic against the A549‐resistant clones and display a lower efficiency to stabilize hTERT G‐quadruplexes. These results lead us to propose that 12459 impairs the splicing machinery of hTERT through stabilization of quadruplexes located in the hTERT intron 6. Differences of selectivity between 12459, BRACO19 and telomestatin for these hTERT quadruplexes may be important to explain their respective activity and inactivity against hTERT splicing.</abstract><note>Received August 23, 2003; Revised November 13, 2003;; Accepted November 26, 2003</note><note type="author-notes">*To whom correspondence should be addressed at UFR de Pharmacie, Université de Reims Champagne‐Ardenne, 51 rue Cognacq‐Jay, 51096 Reims, France. 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