The human OGG1 gene encodes a DNA glycosylase activity catalysing the excision of the mutagenic lesion 7,8-dihydro-8-oxoguanine from oxidatively damaged DNA. The OGG1 gene was localized to chromosome 3p25, a region showing frequent loss of heterozygosity (LOH) in lung and kidney tumours. In this study, we have analysed by RT ± PCR the expression of OGG1 in 25 small cell lung cancers, in 15 kidney carcinomas and the 15 normal kidney counterparts. The results show that OGG1 messenger RNA can be detected in all tumours tested and that no signi®cant di erence was observed in the level of expression between normal and tumoral kidney tissues. Denaturing gradient gel electrophoresis (DGGE) was used to screen this series of human tumours for alterations in the OGG1 cDNA. The study revealed homozygous mutations in three tumours, two from lung and one from kidney. Sequencing analysis of the mutants identi®ed a single base substitution in each of the three cases: two tranversions (GC to TA and TA to AT) and one transition (GC to AT). All three substitutions cause an amino acid change in the hOgg1 protein. For the mutant kidney tumour, the normal tissue counterpart shows a wild-type pro®le. These results suggest a role for OGG1 mutations in the course of the multistage process of carcinogenesis in lung or kidney.Keywords: oxidative DNA damage; DNA repair; missense mutations of OGG1 gene; human lung and kidney cancer; tumour suppressor gene Damage to DNA by oxygen-free radicals is postulated to cause mutations that are associated with the initiation or the progression of human cancers (Breimer, 1990;Loeb, 1997;Beckman and Ames, 1997). Oxidative damage-induced mutations can activate oncogenes or inactivate tumour suppressor genes altering the cell growth control (Fearon, 1997). An oxidatively damaged guanine, 7,, is abundantly produced in DNA as a consequence of the cellular oxidative metabolism or the exposure to ionizing radiation or chemical carcinogens (Dizdaroglu, 1991;Cadet et al., 1997). The presence of 8-OxoG in DNA has been shown to be mutagenic since, while this lesion does not impede DNA chain elongation, it preferentially pairs with adenine during in vitro DNA synthesis (Shibutani et al., 1991). The biological incidence of the presence of 8-OxoG in DNA has been unveiled by the study of two genes in E. coli, fpg (mutM) and mutY (micA) which code for DNA glycosylases that cooperate to prevent the mutagenic e ects of 8-OxoG in DNA (Boiteux et al., 1987;Cabrera et al., 1988;Radicella et al., 1988;Nghiem et al., 1988;Au et al., 1989). Inactivation of either gene leads to a spontaneous mutator phenotype characterized by the exclusive increase in GC to TA transversions (Michaels and Miller, 1992;Grollman and Moriya, 1993;Boiteux and Laval, 1997). In Saccharomyces cerevisiae the OGG1 gene was cloned as the functional eukaryotic homologue of the bacterial fpg gene (Au ret van der Kemp et al., 1996). The yeast Ogg1 protein is a DNA glycosylase/AP lyase which excises 8-OxoG, formamidopyrimidines and incizes apurinic/apyrimid...
Delayed cell death by mitotic catastrophe is a frequent mode of solid tumor cell death after γ-irradiation, a widely used treatment of cancer. Whereas the mechanisms that underlie the early γ-irradiation-induced cell death are well documented, those that drive the delayed cell death are largely unknown. Here we show that the Fas, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and tumor necrosis factor (TNF)-α death receptor pathways mediate the delayed cell death observed after γ-irradiation of breast cancer cells. Early after irradiation, we observe the increased expression of Fas, TRAIL-R and TNF-R that first sensitizes cells to apoptosis. Later, the increased expression of FasL, TRAIL and TNF-α permit the apoptosis engagement linked to mitotic catastrophe. Treatments with TNF-α, TRAIL or anti-Fas antibody, early after radiation exposure, induce apoptosis, whereas the neutralization of the three death receptors pathways impairs the delayed cell death. We also show for the first time that irradiated breast cancer cells excrete soluble forms of the three ligands that can induce the death of sensitive bystander cells. Overall, these results define the molecular basis of the delayed cell death of irradiated cancer cells and identify the death receptors pathways as crucial actors in apoptosis induced by targeted as well as non-targeted effects of ionizing radiation.
A growing body of evidence attributes properties of chemo- and/or radiation-resistance to cancer stem cells (CSCs). Moreover, non-targeted delayed effects such as genomic instability, transmitted through many generations, can be observed in the progeny of surviving irradiated cells. As a consequence, we propose that radiation-resistance properties associated to CSCs could confer a key role to this subpopulation in the transmission of genomic instability. To test this hypothesis, we searched the CSC markers associated to radiation-resistance in breast cancer cell lines and studied the role of the resistant cells in the transmission of genomic instability. First, we show that irradiation induces a 2-4 weeks period of intense cell death leading to the emergence of chromosomal unstable cells during more than 35 population doublings. Then, among seven breast CSC markers, we identify CD24(-/low) labelling as a marker of radiation-resistance. We demonstrate that CD24(+) progeny of irradiated cells exclusively descends from CD24(-/low) cells. Finally, we show that delayed chromosomal instability is only expressed by CD24(+) cells, but is transmitted by stable surviving CD24(-/low) cells. So, for the first time a CSC marker, CD24, is associated with the transmission of genomic instability. This work may assign a new deleterious role to breast CSCs in aggressive recurrence after radiotherapy, as the transmitted genomic instability potentially leads tumour cells to acquire more aggressive characteristics.
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