TERT distal promoter GC islands are critical for telomerase and together with DNMT3B silencing may serve as a senescence-inducing agent in gliomas

buir.contributor.authorŞerifoğlu, Naz
buir.contributor.authorAdams, Michelle
buir.contributor.authorErbaba, Begün
buir.contributor.authorArslan-Ergül, Ayça
buir.contributor.orcidŞerifoğlu, Naz|0000-0003-1228-1375
buir.contributor.orcidErbaba, Begün|0000-0003-0305-6280
buir.contributor.orcidArslan-Ergül, Ayça|0000-0001-7024-907X
dc.citation.epage97en_US
dc.citation.issueNumber4en_US
dc.citation.spage89en_US
dc.citation.volumeNumber36en_US
dc.contributor.authorŞerifoğlu, Naz
dc.contributor.authorAdams, Michelle
dc.contributor.authorErbaba, Begün
dc.contributor.authorArslan-Ergül, Ayça
dc.date.accessioned2023-02-23T16:31:47Z
dc.date.available2023-02-23T16:31:47Z
dc.date.issued2022-08-23
dc.departmentInstitute of Materials Science and Nanotechnology (UNAM)en_US
dc.description.abstractTelomerase is reactivated in the majority of cancers. For instance, in gliomas, it is common that the TERT promoter is mutated. Research on telomere promoter GC islands have been focused primarily on proximal TERT promoter but little is known about the distal promoter. Therefore, in this study, we investigated the proximal and distal TERT promoter, in terms of DNA methylation. We did bisulfite sequencing in zebrafish tissue samples for the distal tert promoter. In the zebrafish brain tissues, we identified a hypomethylation site in the tert promoter, and found that this hypomethylation was associated with aging and shortened telomeres. Through site directed mutagenesis in glioma cell lines, we changed 10 GC spots individually, cloned into a reporter vector, and measured promoter activity. Finally, we silenced DNMT3B and measured telomerase activity along with vidaza and adriamycin treatments. Site directed mutagenesis of glioma cell lines revealed that each of the 10 GC spots are critical for telomerase activity. Changing GC to AT abolished promoter activity in all spots when transfected into glioma cell lines. Then, through silencing of DNMT3B, we observed a reduction in hTERT expression levels, while hTR remained the same, and a major increase in senescence-associated beta-galactosidase activity. Finally, we propose a model regarding the efficacy of two chemotherapeutic drugs, adriamycin and azacytidine, on gliomas. Here, we show that distal TERT promoter is critical; changing even one GC to AT abolishes TERT promoter activity. DNMT3B, a de novo methyltransferase, together with GC islands in distal TERT promoter plays an important role in regulation of telomerase expression and senescence.en_US
dc.description.provenanceSubmitted by Samet Emre (samet.emre@bilkent.edu.tr) on 2023-02-23T16:31:47Z No. of bitstreams: 1 TERT_distal_promoter_GC_islands_are_critical_for_telomerase_and_together_with_DNMT3B_silencing_may_serve_as_a_senescence-inducing_agent_in_gliomas.pdf: 1780870 bytes, checksum: 346d81757ee1f56d689f667cc46bd0ad (MD5)en
dc.description.provenanceMade available in DSpace on 2023-02-23T16:31:47Z (GMT). No. of bitstreams: 1 TERT_distal_promoter_GC_islands_are_critical_for_telomerase_and_together_with_DNMT3B_silencing_may_serve_as_a_senescence-inducing_agent_in_gliomas.pdf: 1780870 bytes, checksum: 346d81757ee1f56d689f667cc46bd0ad (MD5) Previous issue date: 2022-08-23en
dc.identifier.doi10.1080/01677063.2022.2106371en_US
dc.identifier.eissn1563-5260
dc.identifier.urihttp://hdl.handle.net/11693/111651
dc.language.isoEnglishen_US
dc.publisherTaylor & Francis Inc.en_US
dc.relation.isversionofhttps://doi.org/10.1080/01677063.2022.2106371en_US
dc.source.titleJournal of Neurogeneticsen_US
dc.subjectTelomereen_US
dc.subjectTERT promoteren_US
dc.subjectTelomeraseen_US
dc.subjectBrain canceren_US
dc.subjectDNA methylationen_US
dc.titleTERT distal promoter GC islands are critical for telomerase and together with DNMT3B silencing may serve as a senescence-inducing agent in gliomasen_US
dc.typeArticleen_US

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