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Molecular and Cellular Biology, September 2004, p. 8145-8153, Vol. 24, No. 18
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.18.8145-8153.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Spontaneous Mutagenesis Is Enhanced in Apex Heterozygous Mice

Department of Cellular and Structural Biology,¹ Department of Pathology, The University of Texas Health Science Center at San Antonio,² Department of Biology, University of Texas at San Antonio,³ Research Division, South Texas Veteran's Health Care System, San Antonio, Texas,⁶ Biosciences Division, Los Alamos National Laboratories, Los Alamos, New Mexico,⁴ Division of Life Sciences, Lawrence Berkeley National Laboratories, Berkeley, California⁵

Received 8 March 2004/ Returned for modification 27 April 2004/ Accepted 26 June 2004

Germ line DNA directs the development of the next generation and, as such, is profoundly different from somatic cell DNA. Spermatogenic cells obtained from young adult lacI transgenic mice display a lower spontaneous mutant frequency and greater in vitro base excision repair activity than somatic cells and tissues obtained from the same mice. However, spermatogenic cells from old lacI mice display a 10-fold higher mutant frequency. This increased spontaneous mutant frequency occurs coincidentally with decreased in vitro base excision repair activity for germ cell and testicular extracts that in turn corresponds to a decreased abundance of AP endonuclease. To directly test whether a genetic diminution of AP endonuclease results in increased spontaneous mutant frequencies in spermatogenic cell types, AP endonuclease heterozygous (Apex^+/–) knockout mice were crossed with lacI transgenic mice. Spontaneous mutant frequencies were significantly elevated (approximately twofold) for liver and spleen obtained from 3-month-old Apex^+/– lacI⁺ mice compared to frequencies from Apex^+/+ lacI⁺ littermates and were additionally elevated for somatic tissues from 9-month-old mice. Spermatogenic cells from 9-month-old Apex^+/– lacI⁺ mice were significantly elevated twofold compared to levels for 9-month-old Apex^+/+ lacI⁺ control mice. These data indicate that diminution of AP endonuclease has a significant effect on spontaneous mutagenesis in somatic and germ line cells.

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