{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,10,7]],"date-time":"2023-10-07T07:14:33Z","timestamp":1696662873149},"reference-count":33,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2014,7,30]],"date-time":"2014-07-30T00:00:00Z","timestamp":1406678400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NCI-CCR-IRP"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Environ and Mol Mutagen"],"published-print":{"date-parts":[[2014,12]]},"abstract":"<jats:p>The nucleoside reverse transcriptase inhibitor zidovudine (AZT) induces genotoxic damage that includes centrosomal amplification (CA\u2009&gt;\u20092 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\u2010induced DNA damage. We used mesenchymal\u2010derived fibroblasts cultured from C57BL\/6J mice that were null and wild type (WT) for <jats:italic>Xpa<\/jats:italic>, and WT, haploinsufficient and null for <jats:italic>p53<\/jats:italic> (6 different genotypes). Dose\u2010responses for CA formation, in cells exposed to 0, 10, and 100 \u03bcM AZT for 24 hr, were observed in all genotypes except the <jats:italic>Xpa<\/jats:italic><jats:sup>(+\/+)<\/jats:sup><jats:italic>p53<\/jats:italic><jats:sup>(+\/\u2212)<\/jats:sup> cells, which had very low levels of CA, and the <jats:italic>Xpa<\/jats:italic><jats:sup>(\u2212\/\u2212)<\/jats:sup><jats:italic>p53<\/jats:italic><jats:sup>(\u2212\/\u2212)<\/jats:sup> cells, which had very high levels of CA. For CA there was a significant three\u2010way interaction between <jats:italic>Xpa, p53<\/jats:italic>, and AZT concentration, and <jats:italic>Xpa<\/jats:italic><jats:sup>(\u2212\/\u2212)<\/jats:sup> cells had significantly higher levels of CA than <jats:italic>Xpa<\/jats:italic><jats:sup>(+\/+)<\/jats:sup> cells, only for <jats:italic>p53<\/jats:italic><jats:sup>(+\/\u2212)<\/jats:sup> cells. In contrast, the MN and MN\u2009+\u2009chromosomes (MN\u2009+\u2009C) data showed a lack of AZT dose response. The <jats:italic>Xpa<\/jats:italic><jats:sup>(\u2212\/\u2212)<\/jats:sup> cells, with <jats:italic>p53<\/jats:italic><jats:sup>(+\/+)<\/jats:sup> or <jats:sup>(+\/\u2212)<\/jats:sup> genotypes, had levels of MN and MN\u2009+\u2009C higher than the corresponding <jats:italic>Xpa<\/jats:italic><jats:sup>(+\/+)<\/jats: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 <jats:italic>Xpa<\/jats:italic> and <jats:italic>p53<\/jats:italic>. The loss of both genes resulted in high levels of damage, and <jats:italic>p53<\/jats:italic> haploinsufficicency strongly protected <jats:italic>Xpa<\/jats:italic><jats:sup>(+\/+)<\/jats:sup> cells from AZT\u2010induced CA damage. Environ. Mol. Mutagen. 55:719\u2013726, 2014. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.<\/jats:p>","DOI":"10.1002\/em.21889","type":"journal-article","created":{"date-parts":[[2014,7,30]],"date-time":"2014-07-30T09:57:27Z","timestamp":1406714247000},"page":"719-726","source":"Crossref","is-referenced-by-count":0,"title":["Role of nucleotide excision repair and p53 in zidovudine (AZT)\u2010induced centrosomal deregulation"],"prefix":"10.1002","volume":"55","author":[{"given":"Dariya","family":"Momot","sequence":"first","affiliation":[{"name":"Carcinogen\u2010DNA Interactions Section LCBG National Cancer Institute, NIH Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terri A.","family":"Nostrand","sequence":"additional","affiliation":[{"name":"Carcinogen\u2010DNA Interactions Section LCBG National Cancer Institute, NIH Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaarthik","family":"John","sequence":"additional","affiliation":[{"name":"Carcinogen\u2010DNA Interactions Section LCBG National Cancer Institute, NIH Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yvona","family":"Ward","sequence":"additional","affiliation":[{"name":"Cell and Cancer Biology Branch National Cancer Institute, NIH Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seth M.","family":"Steinberg","sequence":"additional","affiliation":[{"name":"Biostatistics and Data Management Section National Cancer Institute, NIH Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Liewehr","sequence":"additional","affiliation":[{"name":"Biostatistics and Data Management Section National Cancer Institute, NIH Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam C.","family":"Poirier","sequence":"additional","affiliation":[{"name":"Carcinogen\u2010DNA Interactions Section LCBG National Cancer Institute, NIH Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ofelia A.","family":"Olivero","sequence":"additional","affiliation":[{"name":"Carcinogen\u2010DNA Interactions Section LCBG National Cancer Institute, NIH Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,7,30]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-3800"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e328329c74e"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2450"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrfmmm.2009.08.005"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/18.12.2327"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/377169a0"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/23.12.2043"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.20280"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2004.12.028"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2008.04.002"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2007.80"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7801121"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0921-8777(94)00061-A"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/24.3.613"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgs247"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi701863u"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.13.5664-5674.2005"},{"key":"e_1_2_8_19_1","unstructured":"NTP.2012. 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