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- Title
Gene-targeted mice lacking the Ung uracil-DNA glycosylase develop B-cell lymphomas.
- Authors
Nilsen, Hilde; Stamp, Gordon; Andersen, Sonja; Hrivnak, Geza; Krokan, Hans E; Lindahl, Tomas; Barnes, Deborah E
- 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.Oncogene (2003) 22, 5381-5386. doi:10.1038/sj.onc.1206860
- Subjects
URACIL; DNA; B cells; LYMPHOMAS; IMMUNOGLOBULINS
- Publication
Oncogene, 2003, Vol 22, Issue 35, p5381
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1206860