Most human carcinogens cause mutations and cancer by damaging DNA directly. A new study by Dmitry Gordenin and colleagues to appear in the July issue of Nature Genetics identifies a different mode of action for cadmium, an environmental hazard and known carcinogen. Cadmium was found to induce mutations in DNA by inhibiting a process called mismatch repair, which is required for the correction of spontaneously occurring mutations in all cells.
Gordenin and colleagues tested several agents for their ability to inhibit mismatch repair in yeast cells. They found that chronic exposure to low, non-lethal doses of cadmium - comparable to levels that can be found in the environment and that accumulate in the human body - increased the level of DNA damage by up to 2,000-fold. A number of lines of evidence suggest that cadmium targets the mismatch repair process, including the molecular ‘signature’ of the observed mutations. The authors also showed that cadmium could inhibit mismatch repair in extracts of human cells, although the specific targets have not yet been identified.
Cadmium is known to accumulate in the human body in the liver, kidney, prostate and lung, with higher levels in the lung found in tobacco smokers. As the level of mismatch repair is an important risk factor for a number of cancers, the authors suggest that the impact of cadmium on mismatch repair in healthy and cancerous human tissues deserves further study.
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(C) Nature Genetics press release.
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