Establishment of DNA repair-deficient or-superproficient mice and their development and molecular basis of genetic instability

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We established the XPA (xeroderma pigmentosum group A) knockout mice by insertion of neo gene into exon 4 of the mouse XPA gene. XPA knockout mice showed neither obvious physical abnormalities nor pathological alterations, but were defective in nucleotide excision repair and highly susceptible to UVB- or DMBA-induced skin carcinogenesis. We cloned a gene responsible for the UV-sensitive rodent mutant cells which belong to the genetic complementation group 5 (ERCC5) and found that the ERCC5 was also a causative gene for XPG.We established XPG knockout mice by insertion of neo gene into the amino terminal region of the mouse XPG gene. The XPG knockout mice were obtained in a Mendelian fashion, but the homozygotes died by the time of weaning, indicating that the XPG gene play an essential role besides nucleotide excision repair. We cloned mouse MGMT (O^6-methyl guanine DNA methyltransferase) gene and mouse MTH1 gene (8-oxo-dGTPase gene) and established MGMT- or MTH1-knockout mice. MGMT knockout mice developed almost normally but the body weight of the MGMT knockout mice was 15% smaller than normal littermates and they were hypersensitive to methylnitrosourea. The homozygotes developed significant decrease of hematopoietic and immune cells and severe erosion of the mucous membrane of the digestive organs. The MTH1 mice did not show high incidence of spontaneous cancers. We cloned mouse homologue of the Rad51 gene and found that the Rad51 knockout homozygotes are lethal in the embryogenesis. We established HITEC mice with which we can detect somatic mutations in the rpsL transgene in the mice. We found that the mutation frequency in the rpsL gene of the spleen, thymus, lung and liver of the HITEC mice was significantly increased after treatment of the mice with methylnitrosourea. Almost all the mutations were G to A transitions.