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Gene-targeted mice lacking the Ung uracil-DNA glycosylase develop B-cell lymphomas

Oncogene volume 22, pages 5381–5386 (2003)Cite this article

Abstract

Mice deficient in the Ung uracil-DNA glycosylase have an increased level of uracil in their genome, consistent with a major role of Ung counteracting U : A base pairs arising by misincorporation of dUMP during DNA replication. A complementary uracil-excising activity apparently acts on premutagenic U : G lesions resulting from deamination of cytosine throughout the genome. However, Ung specifically processes U : G lesions targeted to immunoglobulin variable (V) genes during somatic hypermutation and class-switch recombination. Gene-targeted Ung−/− null mice remained tumour-free and showed no overt pathological phenotype up to ∼12 months of age. We have monitored a large cohort of ageing Ung−/− mice and, beyond 18 months of age, they had a higher morbidity than Ung+/+ controls. Post-mortem analyses revealed pathological changes in lymphoid organs, abnormal lymphoproliferation, and a greatly increased incidence of B-cell lymphomas in older Ung-deficient mice. These are the first data reporting the development of spontaneous malignancies in mice due to deficiency in a DNA glycosylase. Furthermore, they support a specific role for Ung in the immune system, with lymphomagenesis being related to perturbed processing of antibody genes in germinal centre B cells.

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Acknowledgements

We thank Ashfaq Gilkar and Marokh Nohdani for histopathology, Tania Jones for sister chromatid exchange analyses, Michael Bradburn for help with statistical analysis, and Cheryl Young for technical assistance. This work was supported by Cancer Research UK. H Nilsen was the recipient of an EC Marie Curie Fellowship.

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Authors and Affiliations

  1. Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire, EN6 3LD, UK

    Hilde Nilsen, Geza Hrivnak, Tomas Lindahl & Deborah E Barnes

  2. Department of Histopathology, Faculty of Medicine, Imperial College, Du Cane Road, London, W12 0NN, UK

    Gordon Stamp

  3. Institute of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Medical Faculty, Trondheim, N-7489, Norway

    Sonja Andersen & Hans E Krokan

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  1. Hilde Nilsen
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Correspondence to Tomas Lindahl.

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Nilsen, H., Stamp, G., Andersen, S. et al. Gene-targeted mice lacking the Ung uracil-DNA glycosylase develop B-cell lymphomas. Oncogene 22, 5381–5386 (2003). https://doi.org/10.1038/sj.onc.1206860

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