Journal Article

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

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

in Carcinogenesis

Volume 17, issue 6, pages 1215-1220
Published in print June 1996 | ISSN: 0143-3334
Published online June 1996 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.6.1215
ACCELERATED PAPER: Targeted disruption of the DNA repair
                    methyltransferase gene renders mice hypersensitive to alkylating
                    agent

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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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Subjects: Clinical Cytogenetics and Molecular Genetics

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