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

Robert E. Goldsby, Laura E. Hays, Xin Chen, Elise A. Olmsted, William B. Slayton, Gerry J. Spangrude, Bradley D. Preston

Research output: Contribution to journalArticlepeer-review

146 Scopus citations

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 Pold1D400A/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 Pold1D400A/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 Pold1D400A/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.

Original languageEnglish (US)
Pages (from-to)15560-15565
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number24
DOIs
StatePublished - Nov 26 2002
Externally publishedYes

ASJC Scopus subject areas

  • General

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