title: Role of nucleotide excision repair and p53 in zidovudine (AZT)-induced centrosomal deregulation.
abstract: 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 Xpa, and WT, haploinsufficient and null for p53 (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 Xpa((+/+)) p53((+/-)) cells, which had very low levels of CA, and the Xpa((-/-)) p53((-/-)) cells, which had very high levels of CA. For CA there was a significant three-way interaction between Xpa, p53, and AZT concentration, and Xpa((-/-)) cells had significantly higher levels of CA than Xpa((+/+)) cells, only for p53((+/-)) cells. In contrast, the MN and MN + chromosomes (MN + C) data showed a lack of AZT dose response. The Xpa((-/-)) cells, with p53((+/+)) or ((+/-)) genotypes, had levels of MN and MN + C higher than the corresponding Xpa((+/+)) 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 Xpa and p53. The loss of both genes resulted in high levels of damage, and p53 haploinsufficicency strongly protected Xpa((+/+)) cells from AZT-induced CA damage.
authors: Carcinogen-DNA Interactions Section, LCBG, National Cancer Institute, NIH, Bethesda, Maryland.
authors: Dariya
authors: D
authors: Momot
authors: Terri A
authors: TA
authors: Nostrand
authors: Kaarthik
authors: K
authors: John
authors: Yvona
authors: Y
authors: Ward
authors: Seth M
authors: SM
authors: Steinberg
authors: David J
authors: DJ
authors: Liewehr
authors: Miriam C
authors: MC
authors: Poirier
authors: Ofelia A
authors: OA
authors: Olivero
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018385:Centrosome / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015162:Micronucleus Tests; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics; D015215:Zidovudine / Q000633:toxicity*
chemical_list: D016159:Tumor Suppressor Protein p53; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D015215:Zidovudine
keywords: Xpa; centrosomal amplification; micronuclei; micronuclei with whole chromosomes; zidovudine