Giese H, Dollé M E, Hezel A, van Steeg H, Vijg J
Beth Israel Deaconess Medical Center and Harvard Medical School, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USA.
Oncogene. 1999 Feb 4;18(5):1257-60. doi: 10.1038/sj.onc.1202404.
Inheritable mutations in nucleotide excision repair (NER) genes cause cancer-prone human disorders, such as xeroderma pigmentosum, which are also characterized by symptoms of accelerated ageing. To study the impact of NER deficiency on mutation accumulation in vivo, mutant frequencies have been determined in liver and brain of 2-16 month old NER deficient XPA-/-, lacZ hybrid mice. While mutant frequencies in liver of 2-month old XPA-/-, lacZ mice were comparable to XPA+/-, lacZ and the lacZ parental strain animals, by 4 months of age mutant frequencies in the XPA-deficient mice were significantly increased by a factor of two and increased further until the age of 16 months. In brain, mutant frequencies were not found to increase with age. These results show that a deficiency in the NER gene XPA causes an accelerated accumulation of somatic mutations in liver but not in brain. This is in keeping with a higher incidence of spontaneous liver tumors reported earlier for XPA-/- mice after about 15 months of age.
核苷酸切除修复（NER）基因的可遗传突变会导致人类易患癌症的疾病，如着色性干皮病，其特征还包括加速衰老的症状。为了研究NER缺陷对体内突变积累的影响，已在2至16月龄的NER缺陷型XPA-/-、lacZ杂交小鼠的肝脏和大脑中测定了突变频率。虽然2月龄XPA-/-、lacZ小鼠肝脏中的突变频率与XPA+/-, lacZ和lacZ亲本品系动物相当，但到4月龄时，XPA缺陷小鼠中的突变频率显著增加了两倍，并进一步增加直至16月龄。在大脑中，未发现突变频率随年龄增加。这些结果表明，NER基因XPA的缺陷会导致肝脏中体细胞突变的加速积累，但不会导致大脑中体细胞突变的加速积累。这与之前报道的XPA-/-小鼠在约15月龄后自发性肝肿瘤的较高发生率一致。
