Nilsen Hilde, Stamp Gordon, Andersen Sonja, Hrivnak Geza, Krokan Hans E, Lindahl Tomas, Barnes Deborah E
Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK.
Oncogene. 2003 Aug 21;22(35):5381-6. doi: 10.1038/sj.onc.1206860.
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.
缺乏尿嘧啶 - DNA糖基化酶（Ung）的小鼠基因组中尿嘧啶水平升高，这与Ung在抵消DNA复制过程中dUMP错掺入产生的U:A碱基对方面的主要作用一致。一种互补的尿嘧啶切除活性显然作用于全基因组中胞嘧啶脱氨产生的致突变前U:G损伤。然而，Ung在体细胞高频突变和类别转换重组过程中特异性处理靶向免疫球蛋白可变（V）基因的U:G损伤。基因靶向的Ung(-/-) 基因敲除小鼠在大约12个月龄之前一直无肿瘤，且未表现出明显的病理表型。我们监测了一大群衰老的Ung(-/-) 小鼠，在18个月龄之后，它们的发病率高于Ung(+/+) 对照小鼠。尸检分析显示，老年Ung缺陷小鼠的淋巴器官出现病理变化、异常淋巴细胞增殖以及B细胞淋巴瘤的发病率大幅增加。这些是首次报道由于DNA糖基化酶缺陷导致小鼠发生自发性恶性肿瘤的数据。此外，它们支持Ung在免疫系统中的特定作用，淋巴瘤的发生与生发中心B细胞中抗体基因的处理紊乱有关。
