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© 1996 Oxford University Press

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

Teruhisa Tsuzuki 1, Sakumi Kunihiko 1, Akiko Shiraishi 1, Hisaya Kawate 1, Hisato Igarashi 1, Tomoo Iwakuma 1, Yohei Tominaga 1, Shaomin Zhang 2, Seiichiro Shimizu 2, Takatoshi Ishikawa 2, Kenji Nakamura 1, Kazuki Nakao 1, Motoya Katsuki 1 and Mutsuo Sekiguchi 1 3

1Medical Institute of Bioregulation, Kyushu University Fukuoka 812–82
2Department of Pathology, Faculty of Medicine, The University of Tokyo Tokyo 113, Japan

3To whom correspondence should be addressed at: Department of Biochemistry, Medical Institute of Bioregulation, Kyushu University 69, Fukuoka 812–82, Japan

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.


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