@article{allio_donner_preston_2000, title={A comparison of the roles of p53 mutation and AraC inhibition in the enhancement of bleomycin-induced chromatid aberrations in mouse and human cells}, volume={447}, ISSN={["0027-5107"]}, DOI={10.1016/S0027-5107(99)00212-2}, abstractNote={Previous studies have shown that p53 is involved in the repair of bleomycin-induced DNA damage, and that the frequency of bleomycin-induced chromatid aberrations is elevated in G2-treated p53 null transgenic mouse embryo fibroblasts (MEF) as compared to isogenic controls. To further characterize p53-mediated DNA repair, we studied the effect of p53 status on the ability of the DNA repair inhibitor 1-ß-d-arabinofuranosylcytosine (AraC) to sensitize MEF to bleomycin-induced chromatid aberrations. Both p53+/+ and p53−/− MEF were treated in G2 with 0 to 7.5 μg/ml bleomycin in the presence or absence of AraC (5×10−5 M). The frequency of bleomycin-induced chromatid aberrations was significantly higher in p53−/− cells than wild-type cells in the absence of AraC. AraC treatment significantly increased the frequency of bleomycin-induced chromatid aberrations in p53+/+ MEF to the levels in p53−/− (no AraC) but had no effect in p53−/− MEF. These results suggest that an AraC-sensitive DNA repair component is altered or absent in p53−/− cells. Similar results were observed in p53-mutant WTK1 and wild-type TK6 human lymphoblast cells exposed to 0 to 3 μg/ml bleomycin in G2. However, AraC did cause a small increase in bleomycin sensitivity in WTK1 cells. This difference from the p53−/− MEF response may be due to differences in p53-mutant phenotype. To determine whether mutation of p53 alters DNA replication fidelity, p53+/+ and p53−/− MEF were exposed to 0 to 1 μg/ml mitomycin C (MMC). MMC did not induce chromosome aberrations in either cell line treated in G2 but did with the same effectiveness in both cell lines treated in S-phase. Thus, p53 deficiency does not affect DNA replication fidelity or the repair of MMC-induced DNA damage.}, number={2}, journal={MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS}, author={Allio, T and Donner, EM and Preston, RJ}, year={2000}, month={Feb}, pages={227–237} }
 @article{allio_preston_2000, title={Increased sensitivity to chromatid aberration induction by bleomycin and neocarzinostatin results from alterations in a DNA damage response pathway}, volume={453}, ISSN={["0027-5107"]}, DOI={10.1016/S0027-5107(00)00030-0}, abstractNote={DNA damage response pathways coordinate the cellular response to DNA damage. To investigate the roles of tumor suppressor genes in these pathways, human lymphoblastoid cells (wild-type, p53−/−, ATM−/−) were treated for 1 h with 0–3 μg/ml of the radiomimetic compound bleomycin (BLM), and cells treated in G2 were analyzed for chromatid aberrations. BLM-induced aberration frequencies were significantly increased, to the greatest extent in the ATM−/− cells and, to a lesser extent, in the p53−/− cells compared to wild-type cells. These observations are consistent with p53 and ATM acting in a damage response pathway activated by DNA strand breaks. The consequences of disrupting this pathway were further investigated by studies using wortmannin, a PI-3 kinase and DNA repair inhibitor. Wortmannin significantly increased the BLM-induced aberration frequencies in all but the ATM−/− cells, elevating the sensitivity of p53−/− cells to ATM−/− levels and that of wild-type cells to intermediate levels. These differential sensitivities suggest that the ATM phenotype is the result of dual cellular defects, one involving p53 and the other a wortmannin-sensitive component. Similar studies in Brca1+/− and Brca2+/− human lymphoblasts showed no increased sensitization to BLM in the absence of inhibitor, and differential sensitization by wortmannin. To determine if there was any substrate specificity for p53- and ATM-mediated DNA damage responses, chromatid aberrations were assessed in wild-type, p53−/−, and ATM−/− cells exposed to 0–0.4 μg/ml neocarzinostatin (NCS) for 1 h. In contrast to results with BLM, the p53−/− cells exhibited a low sensitivity to NCS-induced aberrations, similar to wild-type, while ATM−/− cells remained highly sensitive. This suggests that the response to BLM- and NCS-induced lesions involves different mechanisms.}, number={1}, journal={MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS}, author={Allio, T and Preston, RJ}, year={2000}, month={Sep}, pages={5–15} }