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

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.