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Molecular and Cellular Biology, November 2007, p. 7669-7682, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00002-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mutation at the Polymerase Active Site of Mouse DNA Polymerase Increases Genomic Instability and Accelerates Tumorigenesis

Ranga N. Venkatesan,¹ Piper M. Treuting,² Evan D. Fuller,¹ Robert E. Goldsby,³ Thomas H. Norwood,¹ Ted A. Gooley,⁴ Warren C. Ladiges,² Bradley D. Preston,¹ and Lawrence A. Loeb^1*

Departments of Pathology,¹ Comparative Medicine, University of Washington, Seattle, Washington 98195,² Fred Hutchinson Cancer Research Center, Clinical Research Division, D5-360, Seattle, Washington 98109,⁴ Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of California, San Francisco, California 94143-0106³

Received 1 January 2007/ Returned for modification 5 February 2007/ Accepted 16 August 2007

Mammalian DNA polymerase (Pol ) is believed to replicate a large portion of the genome and to synthesize DNA in DNA repair and genetic recombination pathways. The effects of mutation in the polymerase domain of this essential enzyme are unknown. Here, we generated mice harboring an L604G or L604K substitution in highly conserved motif A in the polymerase active site of Pol . Homozygous Pold1^L604G/L604G and Pold1^L604K/L604K mice died in utero. However, heterozygous animals were viable and displayed no overall increase in disease incidence, indicative of efficient compensation for the defective mutant polymerase. The life spans of wild-type and heterozygous Pold1^+/L604G mice did not differ, while that of Pold1^+/L604K mice was reduced by 18%. Cultured embryonic fibroblasts from the heterozygous strains exhibited comparable increases in both spontaneous mutation rate and chromosome aberrations. We observed no significant increase in cancer incidence; however, Pold1^+/L604K mice bearing histologically diagnosed tumors died at a younger median age than wild-type mice. Our results indicate that heterozygous mutation at L604 in the polymerase active site of DNA polymerase reduces life span, increases genomic instability, and accelerates tumorigenesis in an allele-specific manner, novel findings that have implications for human cancer.

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* Corresponding author. Mailing address: Department of Pathology, Box 357705, University of Washington, Seattle, WA 98195-7705. Phone: (206) 543-6015. Fax: (206) 543-3967. E-mail: laloeb{at}u.washington.edu

Published ahead of print on 4 September 2007.

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Molecular and Cellular Biology, November 2007, p. 7669-7682, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00002-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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