Nickel mutagenesis: alteration of the MuSVts110 thermosensitive splicing phenotype by a nickel-induced duplication of the 3' splice site.
We investigated DNA damage caused by carcinogenic metals in a murine sarcoma virus (MuSV)-based mutagenicity assay in which mutations targeted to v-mos expression can be selected. Nickel chloride treatment of NRK cells (termed 6m2 cells) infected with MuSVts110, a retrovirus conditionally defective in viral RNA splicing and cell transformation, caused the outgrowth of transformed "revertants" with changes in the MuSVts110 RNA splicing phenotype. Cadmium and chromium treatment of 6m2 cells resulted in the selection of a second class of revertants with what appeared to be frameshift mutations allowing the translation of a readthrough gag-mos protein. In both classes of metal-induced revertants, viral gene expression was distinct from that observed in revertants arising in untreated 6m2 cultures, arguing that metal treatment did not simply enhance the rate of spontaneous reversion. In one representative nickel revertant line the operative nickel-induced mutation affecting MuSVts110 RNA splicing was a duplication of 70 bases surrounding the 3' splice site. The effect of this mutation was to direct splicing to the most downstream of the duplicated 3' sites and concomitantly relax its characteristic thermosensitivity. These data establish the mutagenic potential of nickel and provide the first example of a defined nickel-induced mutation in a mammalian gene.
Chiocca
S M
SM
Department of Tumor Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Sterner
D A
DA
Biggart
N W
NW
Murphy
E C
EC
D000818:Animals; D002104:Cadmium / Q000633:toxicity; D002857:Chromium / Q000633:toxicity; D002872:Chromosome Deletion; D004249:DNA Damage; D004279:DNA, Viral / Q000187:drug effects*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D009152:Mutagenicity Tests; D009532:Nickel / Q000633:toxicity*; D010641:Phenotype; D009053:Sarcoma Viruses, Murine / Q000235:genetics*; D012513:Sarcoma, Experimental / Q000235:genetics* / Q000382:microbiology; D013696:Temperature; D014162:Transfection
D004279:DNA, Viral; D002104:Cadmium; D002857:Chromium; D009532:Nickel