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

摘要

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 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.