ATRX as a Regulator of Telomerase Activity in Cancer Cells

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dc.contributor.advisorBeattie, Tara L.
dc.contributor.advisorCairncross, Gregory J.
dc.contributor.authorBriggs, Sophie
dc.contributor.committeememberRiabowol, Karl T.
dc.contributor.committeememberGrewal, Savraj S.
dc.date2020-06
dc.date.accessioned2020-03-19T15:51:54Z
dc.date.available2020-03-19T15:51:54Z
dc.date.issued2020-03
dc.description.abstractTelomere maintenance is the central process governing cellular immortality. The two distinct pathways – 1) telomerase activity and 2) the alternative lengthening of telomeres (ALT) – result in telomere elongation and allow cells to evade normal cellular ageing mechanisms. Both telomere maintenance pathways can become activated through gene mutations, leading to genetically unstable cells capable of unlimited proliferation. Expression of the chromatin remodeling protein ATRX is lost in almost all ALT+ cancers, suggesting a role for ATRX in ALT repression, however its exact role in telomere maintenance remains unclear. This thesis provides novel evidence suggesting ATRX acts to resolve telomeric G-quadruplexes (G4), thereby facilitating telomerase activity and indirectly repressing ALT. Using RNA interference in human cancer cell lines and a novel DNA ELISA-based technique, the data presented here establish that loss of ATRX expression results in increased G4 at the telomere. This G4 enrichment correlates with a reduction in telomerase activity in vitro which is exacerbated following treatment with the G4 stabilizing agent, Pyridostatin. Further, loss of the full-length ATRX isoform alone does not directly correlate with the ALT phenotype in the selected cell panel. However, a truncated ATRX isoform, ATRXt, was found to be expressed in all selected telomerase+ cells and shown to maintain key functions of the full-length protein. Therefore, alternative ATRX isoforms may act to facilitate telomerase activity through G4 resolution, even in the absence of full-length protein. Taken together, these data provide novel evidence identifying ATRX as an important factor facilitating telomerase-mediated telomere elongation through G4 resolution at the telomere.en_US
dc.identifier.citationBriggs, S. (2020). ATRX as a Regulator of Telomerase Activity in Cancer Cells (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/37641
dc.identifier.urihttp://hdl.handle.net/1880/111740
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectTelomeraseen_US
dc.subjectELISAen_US
dc.subjectCanceren_US
dc.subjectG-quadruplexen_US
dc.subjectG4en_US
dc.subjectATRXen_US
dc.subjectALTen_US
dc.subjectTelomereen_US
dc.subject.classificationBiology--Cellen_US
dc.subject.classificationBiology--Molecularen_US
dc.subject.classificationBiochemistryen_US
dc.titleATRX as a Regulator of Telomerase Activity in Cancer Cellsen_US
dc.typedoctoral thesisen_US
thesis.degree.disciplineMedicine – Biochemistry and Molecular Biologyen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameDoctor of Philosophy (PhD)en_US
ucalgary.item.requestcopytrueen_US
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