Targeted Disruption of the DNA Repair Methyltransferase Gene Renders Mice Hypersensitive to Alkylating Agent

Alkylation of DNA at the O(6)-position of guanine is one of the most critical events leading to induction of mutation as well as to cancer. The enzyme O(6)-methylguanine-DNA methyltransferase repairs this and related lesions in DNA. By means of gene targeting, we established mouse lines deficient in the methyltransferase gene and tissues from these mice contained no methyltransferase activity. Administration of methylnitrosourea to these gene-targeted mice led to early death, and normal mice treated in the same manner showed no untoward effects. In mice given methylnitrosourea treatment, the bone marrow became hypocellular and there was a drastic decrease in the number of leukocytes and platelets, thereby indicating an impaired reproductive capacity of hematopoietic stem cells. Methyltransferase apparently protected these mice from the pancytopenia caused by the alkylating agent.