ACCELERATED PAPER: Targeted disruption of the DNA repair methyltransferase gene renders mice hypersensitive to alkylating agent

Abstract

Alkylation of DNA at the O⁶-position of guanine is one of the most critical events leading to induction of mutation as well as to cancer. The enzyme O⁶-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 numberof 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.