HIV-1 Tat increases cell survival in response to cisplatin by stimulating Rad51 gene expression

Abstract

Tat is an early regulatory protein of human immunodeficiency virus type 1, which plays a central role in the pathogenesis of AIDS by stimulating transcription of the viral genome and impairing several important cellular pathways during the progression of the disease. Here, we investigated the effect of Tat on cell response to DNA damage. Our results indicate that Tat production causes a noticeable increase in the survival rate of PC12 cells upon their treatment with genotoxic agents. Single-cell gel electrophoresis studies revealed reduced DNA breakage in PC12-Tat cells upon cisplatin treatment relative to the control cells. Furthermore, cytogenetic data exhibited less chromosomal damage in Tat-producing cells after recovery from cisplatin treatment, corroborating electrophoretic data. Examination of several proteins involved in the control of DNA repair showed elevated levels of Rad51, a key regulator of homologous recombination in cells expressing Tat. On the other hand, the level of Ku70, one of the components of the nonhomologous end-joining repair pathway, was slightly decreased in cells expressing Tat. Using a fluorescence-based assay, we demonstrated that repair of DNA double-strand breaks via homologous recombination is increased in Tat-producing cells. The results from in vitro nonhomologous end-joining assay revealed a reduced ability of protein extract from PC12-Tat cells compared to PC12 cells in rejoining linearized DNA. These observations ascribe a new role for Tat in host genomic integrity, perhaps by affecting the expression of genes involved in DNA repair.

Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells

“…The histone acetyltransferase HTATIP (HIV-1 Tat interactive protein, 60 kDa), postmeiotic segregation increased 2-like 6 (PMS2L6), general transcription factor IIH, polypeptide 1 (GTF2H1), and the DNA ligase LIG4, showed higher levels of expression in cell lines that are more resistant to oxaliplatin treatment. In fact, at least LIG4 has been shown previously to confer resistance to the related platinum compound cisplatin (Chipitsyna et al, 2004).…”

<i>In Vitro</i> Investigation of DNA Damage Induced by the DNA Cross-Linking Agents Oxaliplatin and Satraplatin in Lymphocytes of Colorectal Cancer Patients

“…Our data from colorectal cancer cells indicated that the proliferation rate index (PRI) decreased significantly up to 1.49 ± 0.83 (p < 0.01) and 1.82 ± 0.22 (p < 0.001) when treated with satraplatin and oxaliplatin in the highest concentration. Interstrand crosslink repair would necessitate both nucleotide excision and recombinational repair pathways [56]. During replication, the decreased DNA synthesis is partially responsible in the chemotherapeutic effect of drugs which form bulky adducts on the DNA.…”

IRS‐1–Rad51 nuclear interaction sensitizes JCV T‐antigen positive medulloblastoma cells to genotoxic treatment

“…Note, however, that in the presence of cisplatin values of Olive tail moments are expectedly lower, and DNA breaks appear much later in comparison to g-irradiation induced DNA damage. 39 Further evaluation of the data in Figures 1c and 1d indicates that not only are the initial levels of DNA damage similar between BsB8 and Bs-1a cells, but the overall DNA repair seems to be unaffected by the presence of JCV T-antigen (compare ''5 min'' and ''15 min'' time points from g-irradiation; 24 and 48 hr time points from cisplatin). This was quite unexpected considering that BsB8 cells are much more sensitive to cisplatin than Bs-1a cells (Figs.…”

“…This is because intra-strand cross-links formed after cisplatin treatment partially prevent the development of typical comets despite of the fact that single and double strand breaks are also present. 39 With this in mind, we performed separate assays for g-irradiation and for cisplatin-induced DNA damage (Fig. 1d).…”