Stress response induced by DNA damage leads to specific, delayed and untargeted mutations |
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Authors: | Jan J. B. Boesen, Sandrine Stuivenberg, Corné H. M. Thyssens, Henk Panneman, Firouz Darroudi, Paul H. M. Lohman Jo W. I. M. Simons |
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Affiliation: | (1) MGC-Department of Radiation Genetics and Chemical Mutagenesis, University of Leiden, Wassenaarseweg 72, NL-2333 AL Leiden, The Netherlands |
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Abstract: | Summary Cells of the mouse T-lymphoma line GRSL13 were treated with 8-methoxy-psoralen plus longwave ultraviolet light (PUVA) under conditions where the biological effects are mainly due to non-persistent DNA crosslinks (PUVA-CL treatment). Fluctuation analysis showed that PUVA-CL treatment resulted in an enhancement of the mutation rate in the progeny of treated cells, which persisted until the eleventh generation after treatment. Since only 5 cross-links are available to account for 52 mutational events observed in the coding region, about 90% of the induced mutational events must have been untargeted. This was confirmed by molecular analysis of these mutations, which showed that 53% of the point mutations arose at sites which are not a target for psoralens. This supports the hypothesis that stress responses may give rise to untargeted mutagenesis. Further support for this hypothesis is provided by the observation that 8-methoxy-psoralen (8-MOP) or UVA alone (both of which are known to induce many pleiotropic effects) each acted as indirect mutagen by enhancing the mutation rate 2–4 fold in the progeny of treated cells. |
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Keywords: | Untargeted mutagenesis Stress response PUVA Strand specificity Mutation spectrum |
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