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Identification of small molecule inhibitors of the human DNA repair enzyme polynucleotide kinase/phosphatase Open Access


Other title
small molecule inhibitors
polynucleotide kinase/phosphatase
DNA repair
Type of item
Degree grantor
University of Alberta
Author or creator
Freschauf, Gary
Supervisor and department
Weinfeld, Michael (Oncology)
Examining committee member and department
Glover, Mark (Biochemistry)
Tuszynski, Jack (Oncology)
Chan, Gordon (Oncology)
Department of Oncology

Date accepted
Graduation date
Master of Science
Degree level
Human polynucleotide kinase/phosphatase (hPNKP) is a bifunctional DNA repair enzyme that phosphorylates DNA 5’-termini and dephosphorylates DNA 3’-termini. hPNKP has been shown to be involved in both single- and double-strand break repair, and cancer cells depleted of hPNKP show significant sensitivity to ionizing radiation and various other genotoxic agents, including the chemotherapeutic drug camptothecin. Based on these findings, we hypothesized that small molecule inhibitors could also potentiate the sensitivity of human tumors to γ-radiation or camptothecin. A12B4C3 was the most effective inhibitor and was able to enhance the radiosensitivity of human A549 lung adenocarcinoma and MDA-MB-231 breast carcinoma cells by a factor of two. Kinetic analysis of A12B4C3 showed it to be a noncompetitive inhibitor. Conformational investigation using circular dichroism, UV difference spectroscopy and fluorescence resonance energy transfer all indicate that A12B4C3 disrupts the secondary structure of PNKP causing an allosteric conformational change resulting in PNKP phosphatase inhibition.
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Citation for previous publication
Journal of Biological Chemistry (2010)
Research (2009)

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