Investigating the mechanisms of telomere maintenance in zebrafish tissues and human brain cancer cell lines

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buir.advisorAdams, Michelle Marie
dc.contributor.authorŞerifoğlu, Naz
dc.date.accessioned2019-09-12T13:43:31Z
dc.date.available2019-09-12T13:43:31Z
dc.date.copyright2019-09
dc.date.issued2019-09
dc.date.submitted2019-09-11
dc.departmentGraduate Program in Neuroscienceen_US
dc.descriptionCataloged from PDF version of article.en_US
dc.descriptionThesis (M.S.): Bilkent University, Department of Neuroscience, İhsan Doğramacı Bilkent University, 2019.en_US
dc.descriptionIncludes bibliographical references (leaves 79-87).en_US
dc.description.abstractTelomeres are nucleoprotein complexes formed at each end of the chromosomes to protect these ends from deterioration. In each round of cellular division, telomeric sequences shorten due to the end replication problem of DNA polymerase. Progressive telomere shortening results in replicative senescence in healthy somatic cells. To evade replicative senescence, cells need to maintain their telomere length either by activating the telomerase enzyme or through the alternative lengthening of telomeres (ALT). Telomerase is a holoenzyme, which is composed of dyskerin, telomerase RNA subunit (TR or TERC), and telomerase catalytic subunit (TERT). Dyskerin and TR are constitutively expressed in all cells but TERT expression is silenced in adult somatic cells. Thus, telomerase activity is dependent on the expression of TERT. Current studies show that TERT re-activation is a common feature of cancer cells and 85-90% of cancers utilize telomerase enzyme in maintaining telomeres to become immortal. Remaining of cancer cells maintain their telomeres by the alternative lengthening of telomeres (ALT), which is a DNA repair pathway dependent mechanism. Current models suggest that ALT is achieved by homology-directed DNA repair, through the interaction of multiple proteins. DNA methylation is regarded as a key player in epigenetic silencing of transcription. DNA methyltransferase inhibitors are currently being used in cancer treatments. Recent studies show that DNA methyltransferases and their expression levels impact both telomerase- and ALT mediated lengthening of telomeres, and have different outcomes in different tissue types. In this study, we worked on the zebrafish brain and human brain cancer cell lines. In zebrafish brain, we observed differences in methylated regions at Sp1 binding site between young and old that can be associated with telomere shortening. By silencing DNMT1 and DNMT3B in brain cancer cell lines, we investigated the changes in gene expression levels of telomerase and ALT related genes, telomerase activity, population doubling time and replicative senescence status. To further investigate TERT regulation, we introduced mutations to the Sp1 binding sites in the promoter region and measured the promoter activity with luciferase assay. Our results show that Sp1 methylation sites in the telomerase promoter region are critical in brain aging, dependent on their position. We propose a therapeutical option for brain aging and tumorigenesis.en_US
dc.description.degreeM.S.en_US
dc.description.statementofresponsibilityby Naz Şerifoğluen_US
dc.embargo.release2020-03-11
dc.format.extentxix, 99 leaves : illustrations, charts ; 30 cm.en_US
dc.identifier.itemidB159209
dc.identifier.urihttp://hdl.handle.net/11693/52427
dc.language.isoEnglishen_US
dc.publisherBilkent Universityen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectAgingen_US
dc.subjectZebrafishen_US
dc.subjectBrain cancersen_US
dc.subjectTelomeraseen_US
dc.subjectTERTen_US
dc.subjectALTen_US
dc.subjectSp1en_US
dc.subjectGene expressionen_US
dc.subjectqTRAPen_US
dc.subjectSite-directed mutagenesisen_US
dc.titleInvestigating the mechanisms of telomere maintenance in zebrafish tissues and human brain cancer cell linesen_US
dc.title.alternativeZebrabalığı dokularında ve insan beyin kanserlerinde telomerlerin sürdürülme mekanizmalarının incelenmesien_US
dc.typeThesisen_US

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Graduate Program in Neuroscience - Master's degree