Gene-targeted mice lacking the Ung uracil-DNA glycosylase develop B-cell lymphomas.
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.
Nilsen
Hilde
H
Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK.
Stamp
Gordon
G
Andersen
Sonja
S
Hrivnak
Geza
G
Krokan
Hans E
HE
Lindahl
Tomas
T
Barnes
Deborah E
DE
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
D014498:Uracil; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D051981:Uracil-DNA Glycosidase