High incidence of epithelial cancers in mice deficient for DNA polymerase δ proofreading

doi:10.1073/pnas.232340999

High incidence of epithelial cancers in mice deficient for DNA polymerase δ proofreading

^*Eccles Institute of Human Genetics and Departments of^† Pediatrics (Division of Pediatric Hematology/Oncology),^§ Oncological Sciences, and ^¶Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112; and^∥ Department of Pathology and National Institute of Environmental Health Sciences Comparative Mouse Genomics Center, University of Washington, Seattle, WA 98195 USA

Edited by Allan H. Conney, Rutgers, State University of New Jersey–New Brunswick, Piscataway, NJ, and approved September 23, 2002 (received for review June 6, 2002)

Abstract

Mutations are a hallmark of cancer. Normal cells minimize spontaneous mutations through the combined actions of polymerase base selectivity, 3′ → 5′ exonucleolytic proofreading, mismatch correction, and DNA damage repair. To determine the consequences of defective proofreading in mammals, we created mice with a point mutation (D400A) in the proofreading domain of DNA polymerase δ (polδ, encoded by the Pold1 gene). We show that this mutation inactivates the 3′ → 5′ exonuclease of polδ and causes a mutator and cancer phenotype in a recessive manner. By 18 months of age, 94% of homozygous Pold1^D400A/D400A mice developed cancer and died (median survival = 10 months). In contrast, only 3–4% of Pold1^+/D400A and Pold1^+/+ mice developed cancer in this time frame. Of the 66 tumors arising in 49 Pold1^D400A/D400A mice, 40 were epithelial in origin (carcinomas), 24 were mesenchymal (lymphomas and sarcomas), and two were composite (teratomas); one-third of these animals developed tumors in more than one tissue. Skin squamous cell carcinoma was the most common tumor type, occurring in 60% of all Pold1^D400A/D400A mice and in 90% of those surviving beyond 8 months of age. These data show that polδ proofreading suppresses spontaneous tumor development and strongly suggest that unrepaired DNA polymerase errors contribute to carcinogenesis. Mice deficient in polδ proofreading provide a tractable model to study mechanisms of epithelial tumorigenesis initiated by a mutator phenotype.

Footnotes

↵ ‡ Present address: Department of Pediatrics, University of California, 505 Parnassus Avenue, San Francisco, CA 94143-0110.
↵ ** To whom correspondence should be addressed. E-mail: bradp{at}u.washington.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:
1. ES, embryonic stem
2. MMR, mismatch repair
3. polδ, DNA polymerase δ
4. SCC, squamous cell carcinoma