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Cadmium is a mutagen that acts by inhibiting mismatch repair

Nature Genetics volume 34, pages 326–329 (2003)Cite this article

Abstract

Most errors that arise during DNA replication can be corrected by DNA polymerase proofreading or by post-replication mismatch repair (MMR). Inactivation of both mutation-avoidance systems results in extremely high mutability that can lead to error catastrophe1,2. High mutability and the likelihood of cancer can be caused by mutations and epigenetic changes that reduce MMR3,4. Hypermutability can also be caused by external factors that directly inhibit MMR. Identifying such factors has important implications for understanding the role of the environment in genome stability. We found that chronic exposure of yeast to environmentally relevant concentrations of cadmium, a known human carcinogen5, can result in extreme hypermutability. The mutation specificity along with responses in proofreading-deficient and MMR-deficient mutants indicate that cadmium reduces the capacity for MMR of small misalignments and base-base mismatches. In extracts of human cells, cadmium inhibited at least one step leading to mismatch removal. Together, our data show that a high level of genetic instability can result from environmental impediment of a mutation-avoidance system.

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Figure 1: The impact of CdCl2 on mutation rates and viability in yeast.
Figure 2: Inhibition of in vitro human strand-specific DNA MMR in a repair-proficient cell extract by cadmium.

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Acknowledgements

We thank S. Jinks-Robertson for yeast strains; J. Sterling, J. Choi and G. Horner for help in conducting experiments; and J. Drake, B. Van Houten, M. Waalkes, T. Petes and J. Wachsman for critically reading the manuscript and for advice.

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Authors and Affiliations

  1. Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, 27709, North Carolina, USA

    Yong Hwan Jin, Alan B Clark, Hanan Al-Refai, Thomas A Kunkel, Michael A Resnick & Dmitry A Gordenin

  2. Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, 27709, North Carolina, USA

    Robbert J C Slebos & Jack A Taylor

  3. Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, 27709, North Carolina, USA

    Jack A Taylor

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  1. Yong Hwan Jin
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Correspondence to Dmitry A Gordenin.

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Jin, Y., Clark, A., Slebos, R. et al. Cadmium is a mutagen that acts by inhibiting mismatch repair. Nat Genet 34, 326–329 (2003). https://doi.org/10.1038/ng1172

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