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Synthetic lethal targeting of polynucleotide kinase/phosphatase and its potential role in directed cancer therapies Open Access


Other title
polynucleotide kinase/phosphatase
synthetic lethality
Type of item
Degree grantor
University of Alberta
Author or creator
Mereniuk, Todd
Supervisor and department
Weinfeld, Michael (Experimental Oncology)
Examining committee member and department
Murray, David (Experimental Oncology)
Weinfeld, Michael (Experimental Oncology)
Chan, Gordon (Experimental Oncology)
Li, Xing-Fang (Laboratory Medicine and Pathology)
Bristow, Robert (Medical Biophysics, Radiation Oncology) - University of Toronto
Department of Oncology
Experimental Oncology
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Synthetic lethality arises when simultaneous disruption of two non-essential, non-allelic genes in the same cell causes lethality. This phenomenon has been shown to occur between proteins involved in DNA repair and much attention to date has focused on poly(ADP-ribose) polymerase and the BRCA proteins. Synthetic lethality holds great promise in the development of tailor-made treatments for each specific patient and as such, there exists a need to expand the repertoire of known synthetic lethal associations in human cells. We intended to identify novel synthetic lethal relationships and show these lethal combinations need not solely rely on the interactions between two DNA repair proteins. We performed an siRNA screen of Qiagen’s druggable genome to identify synthetic lethal partnerships with another DNA repair protein, polynucleotide kinase/phosphatase (PNKP). We identified 14 currently known tumor suppressors showing potential synthetic lethality with PNKP, including the tyrosine-protein phosphatase SHP-1, and the major tumor suppressor PTEN. SHP-1 has been shown to be lost or diminished in ~90% of malignant prostate tissues, 95% of malignant lymphomas and 100% of NK and T cell lymphomas tested, whereas PTEN is the second most frequently lost tumor suppressor in human sporadic cancers. Therefore, targeted disruption of PNKP may be of benefit to a large subset of cancer sufferers. Further investigation into the mechanisms underlying synthetic lethality revealed that depletion of SHP-1 causes an increase in the production of reactive oxygen species. This finding suggests a possible mechanism for synthetic lethality beyond widely accepted models seen with co-disruption of PARP and the BRCA proteins in which reactive oxygen species enhance the level of unrepaired strand breaks. We also demonstrated that PTEN’s cytoplasmic phosphatase function is important to rescue the lethal phenotype upon co-disruption with PNKP. Furthermore, loss of both the 3’ phosphatase and 5’ kinase function of PNKP in double-strand break repair contribute to synthetic lethality. Since tumor suppressor proficient cells can withstand PNKP disruption, only the suppressor protein depleted cancer cells should be sensitive to PNKP inhibition. This allows for the development of a highly selective and patient-specific cancer therapy using the targeted disruption of PNKP with either a small molecule inhibitor of PNKP, or siRNA. Furthermore, since normal tissues should be minimally affected by treatment, side effects typically associated with cancer therapies should be minimized.
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