Modulation of ultraviolet light mutational hotspots by cellular stress.
Stressful treatments of cells provoke broad, transient, changes in cellular physiology and gene expression. In addition to these effects, DNA-damaging agents often induce permanent change in the form of mutations. Mutational patterns in target genes typically show hotspots and coldspots, the molecular basis of which appears to lie in the sequence context of the particular site. We determined the mutational pattern in an ultraviolet light-modified (in vitro) marker gene in a shuttle vector passaged through repair deficient (xeroderma pigmentosum) cells and compared it with patterns obtained from cells exposed to stress imposed by a DNA-damaging agent or a calcium ionophore. We found that the mutational hotspot pattern was altered by both stress treatments. We conclude that the cellular environment can influence the probability of mutagenesis at specific sites and propose that some of these effects on mutagenesis are mediated by alterations in cellular calcium levels.
Seetharam
S
S
Laboratory of Molecular Carcinogenesis, National Cancer Institute, NIH, Bethesda, MD 20892.
Seidman
M M
MM
D001483:Base Sequence; D002118:Calcium / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D004260:DNA Repair / Q000528:radiation effects; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000187:drug effects / Q000528:radiation effects*; D011839:Radiation, Ionizing; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum
D015759:Ionomycin; D008741:Methyl Methanesulfonate; D002118:Calcium