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 cr itical events leading to induction of mutation as well as to cancer, T he enzyme O-6-methylguanine-DNA methyltransferase repairs this and rel ated lesions in DNA, By means of gene targeting, we established mouse lines deficient in the methyltransferase gene and tissues from these m ice contained no methyltransferase activity, Administration of methyln itrosourea to these gene-targeted mice led to early death, and normal mice treated in the same manner showed no untoward effects, In mice gi ven methylnitrosourea treatment, the bone marrow became hypocellular a nd there was a drastic decrease in the number of leukocytes and platel ets, thereby indicating an impaired reproductive capacity of hematopoi etic stem cells, Methyltransferase apparently protected these mice fro m the pancytopenia caused by the alkylating agent.