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Permanent link (DOI): https://doi.org/10.7939/R36T68

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

Descriptions

Other title
Subject/Keyword
small molecule inhibitors
polynucleotide kinase/phosphatase
DNA repair
Type of item
Thesis
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
Department of Oncology
Specialization

Date accepted
2012-05-30T15:11:43Z
Graduation date
2011-11
Degree
Master of Science
Degree level
Master's
Abstract
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.
Language
English
DOI
doi:10.7939/R36T68
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Journal of Biological Chemistry (2010)  http://www.ncbi.nlm.nih.gov/pubmed/19940137Cancer
Research (2009)  http://www.ncbi.nlm.nih.gov/pubmed/19773431

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