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The error-prone DNA polymerase ι provides quantitative resistance to lung tumorigenesis and mutagenesis in mice

Oncogene volume 33, pages 3612–3617 (2014)Cite this article

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Abstract

Opposite undamaged nucleotide T, DNA polymerase ι (Polι) preferentially incorporates G rather than A, violating the Watson–Crick rule. Although the actual biological role of Polι remains enigmatic, we have identified its coding gene as a candidate for pulmonary adenoma resistance 2 (Par2), a mouse quantitative trait locus modulating chemically induced lung tumor susceptibility. Notably, the most tumor-sensitive Par2 allele possessed by the 129X1/SvJ mouse is associated with a loss-of-function mutation in Polι. To determine whether the nonfunctional Polι is responsible for the 129X1/SvJ-specific Par2 phenotype, we knocked out Polι in a C57BL/6J mouse carrying a less tumor-sensitive Par2 allele. Disruption of the C57BL/6J Polι conferred 129X1/SvJ-like sensitivity on the C57BL/6J Par2 locus and increased the in vivo mutation frequency in the lung, providing definitive proof that Polι causes the Par2 effect and inhibits tumorigenesis and mutagenesis, despite its extreme replication infidelity.

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Acknowledgements

We are grateful to Dr Yukari Totsuka and Dr Hitoshi Nakagama for their helpful advice on the gpt delta mouse assay. This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology, and the Smoking Research Foundation of Japan.

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Authors and Affiliations

  1. Department of Pathology, Kochi University School of Medicine, Kochi, Japan

    M Iguchi, M Osanai, Y Hayashi & G-H Lee

  2. Ozgene Pty Ltd, Bentley DC, Western Australia, Australia

    F Koentgen

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  1. M Iguchi
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  2. M Osanai
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  3. Y Hayashi
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  5. G-H Lee
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Correspondence to G-H Lee.

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Iguchi, M., Osanai, M., Hayashi, Y. et al. The error-prone DNA polymerase ι provides quantitative resistance to lung tumorigenesis and mutagenesis in mice. Oncogene 33, 3612–3617 (2014). https://doi.org/10.1038/onc.2013.331

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