Stress response induced by DNA damage leads to specific, delayed and untargeted mutations.
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 cross-links (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.
Boesen
J J
JJ
MGC-Department of Radiation Genetics and Chemical Mutagenesis, University of Leiden, The Netherlands.
Stuivenberg
S
S
Thyssens
C H
CH
Panneman
H
H
Darroudi
F
F
Lohman
P H
PH
Simons
J W
JW
D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000235:genetics*; D004307:Dose-Response Relationship, Radiation; D005434:Flow Cytometry; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D008297:Male; D008730:Methoxsalen / Q000633:toxicity; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000235:genetics*; D009152:Mutagenicity Tests; D009154:Mutation / Q000235:genetics; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D004247:DNA; D007041:Hypoxanthine Phosphoribosyltransferase; D008730:Methoxsalen