Role of nucleotide excision repair and p53 in zidovudine (AZT)‐induced centrosomal deregulation. (30th July 2014)

• Record Type: Journal Article
• Authors: Momot, Dariya; Nostrand, Terri A.; John, Kaarthik; Ward, Yvona; Steinberg, Seth M.; Liewehr, David J.; Poirier, Miriam C.; Olivero, Ofelia A.
• Is Part Of: Environmental and molecular mutagenesis. Volume 55:Number 9(2014:Dec.)
• Page Start: 719
• Page End: 726
• Publication Date: 2014-07-30
• Subjects: Mutagenesis -- Periodicals; Molecular genetics -- Periodicals; Mutagenèse -- Périodiques; Mutagenèse chimique -- Périodiques; Mutation -- Périodiques; Maladies de l'environnement -- Périodiques; Génétique moléculaire -- Périodiques; 576.542
• DOI: 10.1002/em.21889
• Languages: English
• ISSNs: 0893-6692

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>The nucleoside reverse transcriptase inhibitor zidovudine (AZT) induces genotoxic damage that includes centrosomal amplification (CA > 2 centrosomes/cell) and micronucleus (MN) formation. Here we explored these end points in mice deficient in DNA repair and tumor suppressor function to evaluate their effect on AZT‐induced DNA damage. We used mesenchymal‐derived fibroblasts cultured from C57BL/6J mice that were null and wild type (WT) for <italic>Xpa</italic>, and WT, haploinsufficient and null for <italic>p53</italic> (6 different genotypes). Dose‐responses for CA formation, in cells exposed to 0, 10, and 100 μM AZT for 24 hr, were observed in all genotypes except the <italic>Xpa</italic><sup>(+/+)</sup><italic>p53</italic><sup>(+/−)</sup> cells, which had very low levels of CA, and the <italic>Xpa</italic><sup>(−/−)</sup><italic>p53</italic><sup>(−/−)</sup> cells, which had very high levels of CA. For CA there was a significant three‐way interaction between <italic>Xpa, p53</italic>, and AZT concentration, and <italic>Xpa</italic><sup>(−/−)</sup> cells had significantly higher levels of CA than <italic>Xpa</italic><sup>(+/+)</sup> cells, only for <italic>p53</italic><sup>(+/−)</sup> cells. In contrast, the MN and MN + chromosomes (MN + C) data showed a lack of AZT dose response. The <italic>Xpa</italic><sup>(−/−)</sup> cells, with <italic>p53</italic><sup>(+/+)</sup> or <sup>(+/−)</sup> genotypes, had levels of MN and MN + C higher than the corresponding <italic>Xpa</italic><sup>(+/+)</sup> cells. The data show that CA is a major event induced by exposure to AZT in these cells, and that there is a complicated relationship between AZT and CA formation with respect to gene dosage of <italic>Xpa</italic> and <italic>p53</italic>. The loss of both genes resulted in high levels of damage, and <italic>p53</italic> haploinsufficicency strongly protected <italic>Xpa</italic><sup>(+/+)</sup> cells from AZT‐induced CA damage. Environ. Mol. Mutagen. 55:719–726, 2014. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.</p> </abstract>