The synthetic dosage lethality between hTERT and DNA damage response associated genes

Cancer cells within the same tumour can exhibit diverse genetic profiles, a phenomenon known as tumour heterogeneity. As a result, certain cancer therapies may fail to target the entire tumor, leading to suboptimal treatment responses. Consequently, it is of paramount importance to identify common characteristics of cancer cells that are absent in non-cancerous cells. 85-90% of primary cancer cells overexpress hTERT. Under normal conditions, the expression of this gene is usually tightly repressed. Cells that do not express hTERT will experience telomere shortening during each cellular division, and eventually, the shortened state of the telomeres will trigger apoptosis. The overexpression of hTERT allows a cancer cell to bypass this limitation, leading to cell immortality. While hTERT appears to be a promising target for cancer therapeutics, previous research has shown that directly inhibiting the enzyme often results in significant off target effects and a considerable lag time between treatment and cancer cell death. To address issues associated with directly inhibiting hTERT, this project uses synthetic dosage lethality (SDL) to indirectly inhibit its activity. SDL occurs when the overexpression of one gene becomes lethal, only when combined with the inhibition of another gene (known as the SDL partner). If only one of these two conditions are met, there is no lethality. This method allows for the selective targeting of cancer cells overexpressing hTERT with minimal harm to non-cancerous cells. Outside of its canonical role of telomere lengthening, hTERT has also been shown to influence the regulation of heterochromatin, the nucleolus, and the DNA damage response. Therefore, we hypothesized that genes whose functionality also lies in these areas could be validated as hTERT SDL partners. The aim of this project was to validate 5 potential hTERT SDL partners from a list of pre-screened genes whose functions overlapped with hTERT in these areas. From the initial 5 candidates, genetic assay validated PRMT5 and GNB1L as hTERT SDL partners. The PRMT5-hTERT SDL relationship was then recapitulated via the use of direct PRMT5 protein inhibitors. We also observed that the PRMT5-hTERT SDL relationship influenced the progression of a cell through mitotic phases. While cancer research into PRMT5 is not novel, this project represents the first time that it has been studied in an hTERT SDL-dependent manner.

Name thesis:degree_name

Master of Science (M.Sc.)

Level thesis:degree_level

Masters

Discipline thesis:degree_discipline

Anatomy, Physiology, and Pharmacology

Grantor

University of Saskatchewan

Year dc:date.issued

2026

Author dc:creator

• Lazell-Wright, Mary

Advisors dc:contributor.advisor

• Vizeacoumar, Franco
• Freywald, Andrew

Committee members dc:contributor.committeemember

• Eames, Brian
• Krishnan, Anand
• Xiao, Wei

• cancer
• tumour heterogeneity
• DNA damage response
• hTERT
• Synthetic dosage lethality

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10388/18737

OAI identifier oai:identifier

oai:harvest.usask.ca:10388/18737