title: 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 approximately 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.
authors.affiliation: Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK.
authors.forename: Hilde
authors.initials: H
authors.lastname: Nilsen
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.forename: Sonja
authors.initials: S
authors.lastname: Andersen
authors.forename: Geza
authors.initials: G
authors.lastname: Hrivnak
authors.forename: Hans E
authors.initials: HE
authors.lastname: Krokan
authors.forename: Tomas
authors.initials: T
authors.lastname: Lindahl
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Barnes
mesh_terms: D000818:Animals; D045647:DNA Glycosylases; D018390:Gene Targeting; D007150:Immunohistochemistry; D008221:Lymphoid Tissue / Q000503:physiopathology; D016393:Lymphoma, B-Cell / Q000209:etiology / Q000235:genetics*; D051379:Mice; D009699:N-Glycosyl Hydrolases / Q000172:deficiency / Q000235:genetics*; D014498:Uracil / Q000378:metabolism; D051981:Uracil-DNA Glycosidase
chemical_list: D014498:Uracil; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D051981:Uracil-DNA Glycosidase