Poly(ADP-ribose) polymerase (PARP), 1 EC 2.4.2.30) a DNA repair-associated enzyme is involved in two diametrically opposite responses to DNA damage, i.e. DNA repair along with other survival responses at lower levels of DNA damage and cell death responses after saturating levels of DNA damage. One of the immediate responses to DNA damage in the higher eukaryotic cells is catalytic activation of PARP, which results in consumption of NAD and formation of the polymers of ADPribose (pADPr) on PARP itself and a few selected nuclear proteins that are involved in chromatin architecture and DNArelated metabolisms. This rapid reaction by PARP has been implicated in DNA base excision repair and in the maintenance of genomic integrity after DNA damage (reviewed in Refs.
Tumorigenicity and radiosensitivity of related cell lines expressing distinct p53 mutants were analyzed in parallel with key components of the antioxidant metabolic pathway. Six sublines deriving from the same parental cell population and expressing either the mutant p53K130R or p53V270F were investigated. Both mutations abrogate the transcriptional activity of p53 as well as its ability to induce apoptosis. The cells expressing p53K130R showed a higher tumorigenicity and a higher radiosensitivity than those expressing p53V270F. An increase in tumorigenicity was associated with a decrease in manganese-containing superoxide dismutase activity, and with further decreases in the glutathione content and glutathione peroxidase (GPX) activity. A positive correlation was found between GPX activity, glutathione content and cell survival following ionizing irradiation. The fact that sister cell lines exhibit different tumorigenicity and radiosensitivity while expressing a mutant p53 further supports the notion that knowledge of p53 status is not sufficient to predict tumor outcome, especially the response to irradiation. A better understanding of antioxidant defenses might be more informative.
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