Polynucleotide Kinase as a Potential Target for Enhancing Cytotoxicity by Ionizing Radiation and Topoisomerase I Inhibitors

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)


Volume 16, 12 Issues, 2016


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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex
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Polynucleotide Kinase as a Potential Target for Enhancing Cytotoxicity by Ionizing Radiation and Topoisomerase I Inhibitors



Anti-Cancer Agents in Medicinal Chemistry, 8(4): 358-367.

Author(s): N. K. Bernstein, F. Karimi-Busheri, A. Rasouli-Nia, R. Mani, G. Dianov, J. N.M. Glover and M Weinfeld.

Affiliation: Experimental Oncology,Cross Cancer Institute, 11560 University Ave, Edmonton, Alberta T6G 1Z2,Canada.

Abstract

The cytotoxicity of many antineoplastic agents is due to their capacity to damage DNA and there is evidence indicating that DNA repair contributes to the cellular resistance to such agents. DNA strand breaks constitute a significant proportion of the lesions generated by a broad range of genotoxic agents, either directly, or during the course of DNA repair. Strand breaks that are caused by many agents including ionizing radiation, topoisomerase I inhibitors, and DNA repair glycosylases such as NEIL1 and NEIL2, often contain 5- hydroxyl and/or 3-phosphate termini. These ends must be converted to 5-phosphate and 3-hydroxyl termini in order to allow DNA polymerases and ligases to catalyze repair synthesis and strand rejoining. A key enzyme involved in this end-processing is polynucleotide kinase (PNK), which possesses two enzyme activities, a DNA 5-kinase activity and a 3-phosphatase activity. PNK participates in the single-strand break repair pathway and the non-homologous end joining pathway for double-strand break repair. RNAi-mediated down-regulation of PNK renders cells more sensitive to ionizing radiation and camptothecin, a topoisomerase I inhibitor. Structural analysis of PNK revealed the protein is composed of three domains, the kinase domain at the C-terminus, the phosphatase domain in the centre and a forkhead associated (FHA) domain at the N-terminus. The FHA domain plays a critical role in the binding of PNK to other DNA repair proteins. Thus each PNK domain may be a suitable target for small molecule inhibition to effectively reduce resistance to ionizing radiation and topoisomerase I inhibitors.

Keywords:

DNA damage, DNA repair, small molecule inhibitors, polynucleotide kinase, FHA, kinase, phosphatase.



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Article Details

Volume: 8
Issue Number: 4
First Page: 358
Last Page: 367
Page Count: 10
DOI: 10.2174/187152008784220311
Price: $58
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