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Abstract 2980: Role of XPA and p53 genes in the induction of centrosomal amplification in mice exposed to Zidovudine (AZT)

In cultured cells, exposure to the highly-effective nucleoside reverse transcriptase inhibitor (NRTI) Zidovudine (AZT) induces genomic instability, causing cell cycle arrest, micronuclei, sister chromatid exchanges, and shortened telomeres. In previous studies, we demonstrated for the first time tha...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2010-04, Vol.70 (8_Supplement), p.2980-2980
Main Authors: Nostrand, Terri A., Momot, Dariya, Poirier, Miriam C., Olivero, Ofelia A.
Format: Article
Language:English
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Summary:In cultured cells, exposure to the highly-effective nucleoside reverse transcriptase inhibitor (NRTI) Zidovudine (AZT) induces genomic instability, causing cell cycle arrest, micronuclei, sister chromatid exchanges, and shortened telomeres. In previous studies, we demonstrated for the first time that AZT induced centrosomal amplification (defined as > 2 centrosomes /cell), a novel manifestation of genotoxicity. Here, bone marrow cells from wild type C57BL/6J mice and their transgenic counterparts with genotypes XPA −/− p53 +/+, XPA−/−p53 +/− and XPA−/−p53 −/−, were cultured in vitro to obtain homogeneous populations of mesenchymal-derived fibroblasts. Wild type, and DNA repair- / p53-deficient cells (n=3/group) were exposed to 0, 10 or 100 μM AZT for 24 hr, and centrosomal amplification was examined by immunohistochemical (IHC) staining with an anti-pericentrin antibody. Values for centrosomal amplification (% of cells with ≥2 centrosomes/cell) were 12.2, 15.2 and 19.7% in wild type (XPA +/+ p53 +/+) cells exposed to 0, 10 or 100 μM AZT, respectively. Values for centrosomal amplification were 18.0, 28.7 and 33.9 % for XPA −/− p53 +/+cells, and 21.6, 29.3 and 39.5% for XPA−/−p53 +/− cells, after exposure to 0, 10 and 100 μM AZT, respectively. For XPA−/−p53 −/− cells there were 18.4, 22.9 and 29.0% of cells with centrosomal amplification after exposure to 0, 10 and 100 µM AZT, respectively. Statistical analysis (by ANOVA) showed significance between each of the three transgenic groups, when compared to the wild type cells (p= 0.0025). The data suggest that loss of both XPA alleles confers genomic instability, but that additional loss of p53 does not further enhance instability. Whereas nucleotide excision repair is not considered to impact NRTI intracellular processing, these data would argue that lack of intact nucleotide excision repair enhances genomic instability in AZT-exposed cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2980.
ISSN:0008-5472
1538-7445
DOI:10.1158/1538-7445.AM10-2980