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Effects of novel inhibitors of poly(ADP-ribose) polymerase-1 and the DNA-dependent protein kinase on enzyme activities and DNA repair

Lookup NU author(s): Dr Stephany Veuger, Professor Nicola Curtin, Emeritus Professor Barbara Durkacz

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Abstract

DNA-dependent protein kinase (DNA-PK) and poly (ADP-ribose) polymerase-1 (PARP-1) participate in nonhomologous end joining and base excision repair, respectively, and are key determinants of radio- and chemo-resistance. Both PARP-1 and DNA-PK have been identified as therapeutic targets for anticancer drug development. Here we investigate the effects of specific inhibitors on enzyme activities and DNA double-strand break (DSB) repair. The enzyme activities were investigated using purified enzymes and in permeabilized cells. Inhibition, or loss of activity, was compared using potent inhibitors of DNA-PK (NU7026) and PARP-1 (AG14361), and cell lines proficient or deficient for DNA-PK or PARP-1. Inactive DNA-PK suppressed the activity of PARP-1 and vice versa. This was not the consequence of simple substrate competition, since DNA ends were provided in excess. The inhibitory effect of DNA-PK on PARP activity was confirmed in permeabilized cells. Both inhibitors prevented ionizing radiation-induced DSB repair, but only AG14361 prevented single-strand break repair. An increase in DSB levels caused by inhibition of PARP-1 was shown to be caused by a decrease in DSB repair, and not by the formation of additional DSBs. These data point to combined inhibition of PARP-1 and DNA-PK as a powerful strategy for tumor radiosensitization.


Publication metadata

Author(s): Veuger SJ, Curtin NJ, Smith G, Durkacz BW

Publication type: Article

Publication status: Published

Journal: Oncogene

Year: 2004

Volume: 23

Issue: 44

Pages: 7322-7329

Print publication date: 23/09/2004

ISSN (print): 0950-9232

ISSN (electronic): 1476-5594

URL: http://dx.doi.org/10.1038/sj.onc.1207984

DOI: 10.1038/sj.onc.1207984

PubMed id: 15286704


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