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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<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>
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<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>
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<notesStmt><note>Received August 23, 2003; Revised November 13, 2003;; Accepted November 26, 2003</note>
<note>*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: jf.riou@univ‐reims.fr</note>
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<author xml:id="author-5"><persName><forename type="first">Jean‐Louis</forename>
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<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>
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Onco‐Pharmacologie and</aff>
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EA3306, IFR53, UFR de Pharmacie, Université de Reims Champagne‐Ardenne, 51096 Reims, France,</aff>
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Laboratoire de Biophysique, INSERM U565, CNRS UMR 5153, Muséum National d’Histoire Naturelle USM 0503, 75005, Paris, France and</aff>
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Aventis Pharma SA, Centre de Recherche de Paris, 94403, Vitry sur Seine, France</aff>
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<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>
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<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>
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</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>
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<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>
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</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>
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<originInfo><publisher>Oxford University Press</publisher>
<dateIssued encoding="w3cdtf">2004-01-16</dateIssued>
<copyrightDate encoding="w3cdtf">2004</copyrightDate>
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<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. Tel: +33 326 91 80 13; Fax: +33 326 91 37 30; Email: jf.riou@univ‐reims.fr</note>
<relatedItem type="host"><titleInfo><title>Nucleic Acids Research</title>
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<titleInfo type="abbreviated"><title>Nucl. Acids Res.</title>
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<genre type="journal">journal</genre>
<identifier type="ISSN">0305-1048</identifier>
<identifier type="eISSN">1362-4962</identifier>
<identifier type="PublisherID">nar</identifier>
<identifier type="PublisherID-hwp">nar</identifier>
<identifier type="PublisherID-nlm-ta">Nucleic Acids Res</identifier>
<part><date>2004</date>
<detail type="volume"><caption>vol.</caption>
<number>32</number>
</detail>
<detail type="issue"><caption>no.</caption>
<number>1</number>
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<extent unit="pages"><start>371</start>
<end>379</end>
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