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). Doseresponses for CA formation, in cells exposed to 0, 10, and 100 lM AZT for 24 hr, were observed in all genotypes except the Xpa (1/1) p53 (1/2) cells, which had very low levels of CA, and the Xpa (2/2) p53 (2/2) 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 (2/2) cells had significantly higher levels of CA than Xpa (1/1) cells, only for p53 (1/2) cells. In contrast, the MN and MN 1 chromosomes (MN 1 C) data showed a lack of AZT dose response. The Xpa (2/2) cells, with p53 (1/1) or (1/2) genotypes, had levels of MN and MN 1 C higher than the corresponding Xpa (1/1) 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 (1/ 1) 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.Key words: zidovudine; micronuclei; micronuclei with whole chromosomes; centrosomal amplification; Xpa Additional Supporting Information may be found in the online version of this article.

Role of DNA Repair Pathways in Response to Zidovudine-induced DNA Damage in Immortalized Human Liver THLE2 Cells

“…In the current study, the expression of XPC and level of GTF2H1 were increased in a dose-related manner in AZT treated THLE2 cells. In addition, a protective role of the NER pathway against aneuploidy and centrosomal aberrations induced by AZT treatment has been demonstrated in a transgenic mouse model (17,45). These observations are consistent with our hypothesis that the NER pathway is the primary mechanism to remove AZT incorporated into the DNA of both malignant and immortalized normal human hepatocytes.…”

Estudo clínico de sarcoma de Kaposi em pacientes com HIV/AIDS, de 1985-1994 e 2005-2014

“…: células fusiformes ou spindle cells) e a angiogênese. [32][33][34][35][36][37][38][39][40] Em pacientes com HIV/AIDS e SK, o tumor pode manter-se estável e sem repercussões significativas ou progredir, o que ocorre aproximadamente em metade dos pacientes, os quais evoluem para a forma disseminada com envolvimento cutâneo e visceral. 22,33 Nosso estudo foi consoante com a literatura, 20,22 encontrando predominância na manifestação disseminada em ambos os cortes temporais.…”

“…Outra possível explicação para esse fenômeno é que os antirretrovirais podem causar danos no genoma humano, aumentando o risco de desenvolvimento de neoplasias. [36][37][38][39] Vários estudos exploraram a possibilida-de da contribuição dos fatores genéticos do hospedeiro, incluindo polimorfismos de genes de resposta inflamatória e imunológica. Especula-se que o SK está associado a polimorfismos nos promotores da IL-6 e da FcγRIIIA, o que pode influenciar no desenvolvimento de SK em homens infectados pelo HIV.…”

Assessment of the Genotoxic Potential of Azidothymidine in the Comet, Micronucleus, and Pig-a Assay

“…Some evidence that these buds are precursors of micronuclei containing specific chromosomes was reported (Fenech et al, 2011;Shimizu, 2011;Shimizu et al, 1998). Furthermore, it was demonstrated that AZT exposure can result in centrosomal amplification, leading to chromosome misaggregation and thus aneuploidy (Borojerdi et al, 2009;Momot et al, 2010).…”