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Molecular and Cellular Biology, October 1998, p. 5828-5837, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Alkylpurine-DNA-N-Glycosylase Knockout Mice Show Increased Susceptibility to Induction of Mutations by Methyl Methanesulfonate

Rhoderick H. Elder,1,* Jacob G. Jansen,2 Robert J. Weeks,1 Mark A. Willington,1 Bryan Deans,1,dagger Amanda J. Watson,1 Kurt J. Mynett,1 John A. Bailey,1 Donald P. Cooper,1,Dagger Joseph A. Rafferty,1 Mel C. Heeran,1 Susan W. P. Wijnhoven,2 Albert A. van Zeeland,2 and Geoffrey P. Margison1

CRC Section of Genome Damage and Repair, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester M20 4BX, United Kingdom,1 and MGC---Department of Radiation Genetics and Chemical Mutagenesis, Leiden University, 2333 AL Leiden, The Netherlands2

Received 31 March 1998/Returned for modification 15 May 1998/Accepted 20 July 1998

Alkylpurine-DNA-N-glycosylase (APNG) null mice have been generated by homologous recombination in embryonic stem cells. The null status of the animals was confirmed at the mRNA level by reverse transcription-PCR and by the inability of cell extracts of tissues from the knockout (ko) animals to release 3-methyladenine (3-meA) or 7-methylguanine (7-meG) from 3H-methylated calf thymus DNA in vitro. Following treatment with DNA-methylating agents, increased persistence of 7-meG was found in liver sections of APNG ko mice in comparison with wild-type (wt) mice, demonstrating an in vivo phenotype for the APNG null animals. Unlike other null mutants of the base excision repair pathway, the APNG ko mice exhibit a very mild phenotype, show no outward abnormalities, are fertile, and have an apparently normal life span. Neither a difference in the number of leukocytes in peripheral blood nor a difference in the number of bone marrow polychromatic erythrocytes was found when ko and wt mice were exposed to methylating or chloroethylating agents. These agents also showed similar growth-inhibitory effects in primary embryonic fibroblasts isolated from ko and wt mice. However, treatment with methyl methanesulfonate resulted in three- to fourfold more hprt mutations in splenic T lymphocytes from APNG ko mice than in those from wt mice. These mutations were predominantly single-base-pair changes; in the ko mice, they consisted primarily of ATright-arrowTA and GCright-arrowTA transversions, which most likely are caused by 3-meA and 3- or 7-meG, respectively. These results clearly show an important role for APNG in attenuating the mutagenic effects of N-alkylpurines in vivo.

* Corresponding author. Mailing address: CRC Section of Genome Damage and Repair, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester, M20 4BX, United Kingdom. Phone: (44) 161-446-3027. Fax: (44) 161-446-3109. E-mail: RElder{at}picr.man.ac.uk.

dagger Present address: Radiation and Genome Stability Unit, Medical Research Council, Harwell, Didcot, Oxfordshire OX11 0RD, United Kingdom.

Dagger Micromass UK Ltd., Wythenshawe, Manchester M23 9LZ, United Kingdom.

Molecular and Cellular Biology, October 1998, p. 5828-5837, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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