Accelerated accumulation of somatic mutations in mice deficient in the nucleotide excision repair gene XPA

Abstract

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.