Library Open Repository

Modulation of DNA polymerase beta-dependent base excision repair in cultured human cells after low dose exposure to arsenite

Downloads

Downloads per month over past year

Sykora, P and Snow, ET (2008) Modulation of DNA polymerase beta-dependent base excision repair in cultured human cells after low dose exposure to arsenite. Toxicology and Applied Pharmacology, 228 (3). pp. 385-394. ISSN 0041-008X

[img] PDF
Sykora-Snow-TAAP-08.pdf | Request a copy
Full text restricted
Available under University of Tasmania Standard License.

Abstract

Base excision repair (BER) is crucial for development and for the repair of endogenous DNA damage. However, unlike nucleotide excision repair, the regulation of BER is not well understood. Arsenic, a well-established human carcinogen, is known to produce oxidative DNA damage, which is repaired primarily by BER, while high doses of arsenic can also inhibit DNA repair. However, the mechanism of repair inhibition by arsenic and the steps inhibited are not well defined. To address this question we have investigated the regulation of DNA polymerase β (Pol β) and AP endonuclease (APE1), in response to low, physiologically relevant doses of arsenic. GM847 lung fibroblasts and HaCaT keratinocytes were exposed to sodium arsenite, As(III), and mRNA, protein levels and BER activity were assessed. Both Pol β and APE1 mRNA exhibited significant dose-dependant down regulation at doses of As(III) above 1 µM. However, at lower doses Pol β mRNA and protein levels, and consequently, BER activity were significantly increased. In contrast, APE1 protein levels were only marginally increased by low doses of As(III) and there was no correlation between APE1 and overall BER activity. Enzyme supplementation of nuclear extracts confirmed that Pol β was rate limiting. These changes in BER correlated with overall protection against sunlight UV-induced toxicity at low doses of As(III) and produced synergistic toxicity at high doses. The results provide evidence that changes in BER due to low doses of arsenic could contribute to a non-linear, threshold dose response for arsenic carcinogenesis.

Item Type: Article
Keywords: AP endonuclease, DNA polymerase β, arsenic, BER, hormesis
Journal or Publication Title: Toxicology and Applied Pharmacology
Page Range: pp. 385-394
ISSN: 0041-008X
Identification Number - DOI: 10.1016/j.taap.2007.12.019
Additional Information: The definitive version is available at http://www.sciencedirect.com
Date Deposited: 24 Apr 2008 03:35
Last Modified: 18 Nov 2014 03:39
URI: http://eprints.utas.edu.au/id/eprint/6215
Item Statistics: View statistics for this item

Repository Staff Only (login required)

Item Control Page Item Control Page