Evaluating the Phenotypic Consequences of DNA-PKcs Deficiency

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dc.contributor.advisorLees-Miller, Susan
dc.contributor.authorKenny, Jacey
dc.contributor.committeememberBillon, Pierre
dc.contributor.committeememberMoorhead, Gregory
dc.date2025-02
dc.date.accessioned2025-01-17T23:02:31Z
dc.date.available2025-01-17T23:02:31Z
dc.date.issued2025-01-14
dc.description.abstractDNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a serine/threonine protein kinase with a well-established role in the repair of DNA double strand breaks. Similarly, Ataxia-Telangiectasia Mutated (ATM) is a protein kinase that plays a central role in downstream signalling response to DNA damage. DNA-PKcs and ATM are members of the phosphatidylinositol 3-kinase-like protein kinase (PIKK) family, which serve critical roles in the cellular response to DNA damage. To better understand the non-canonical roles of DNA-PKcs and ATM, our lab generated human cell lines with CRISPR/Cas9-mediated disruption of these proteins, marking the starting point of my project. My work demonstrates that loss of DNA-PKcs and/or ATM expression results in slower proliferation compared to parental cells, while inhibition of DNA-PKcs or ATM kinase activity had a comparatively minor effect on cell proliferation. My data suggests that this phenotype is not due to increased apoptosis, endogenous DNA damage or cell cycle defects. Comparison of the metabolite profiles of the matched control and CRISPR cell lines suggested enrichment of amino acids in the HeLa CRISPR DNA-PKcs cells which led me to hypothesize that the CRISPR cell lines have a reduced rate of protein translation. I present evidence that cells deficient in DNA-PKcs and ATM exhibit impaired global, new protein translation, revealing a potentially novel mechanism for the slow growth phenotype. This work adds to a growing body of evidence encouraging further exploration of DNA-PKcs and ATM as therapeutic targets in cancer and other diseases.
dc.identifier.citationKenny, J. (2025). Evaluating the phenotypic consequences of DNA-PKcs deficiency (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.
dc.identifier.urihttps://hdl.handle.net/1880/120478
dc.language.isoen
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgary
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.
dc.subject.classificationBiology--Molecular
dc.subject.classificationBiochemistry
dc.titleEvaluating the Phenotypic Consequences of DNA-PKcs Deficiency
dc.typemaster thesis
thesis.degree.disciplineMedicine – Biochemistry and Molecular Biology
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameMaster of Science (MSc)
ucalgary.thesis.accesssetbystudentI require a thesis withhold – I need to delay the release of my thesis due to a patent application, and other reasons outlined in the link above. I have/will need to submit a thesis withhold application.
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