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 polymerase base selectivity, 3′ → 5′ exonucleolytic proofreading, mismatch correction, and DNA damage repair. To determine consequences defective proofreading in mammals, we created mice with point mutation (D400A) domain δ (polδ, encoded by Pold1 gene). We show that this inactivates exonuclease polδ causes mutator cancer phenotype recessive manner. By 18 months age, 94% homozygous Pold1D400A/D400A developed died (median survival = 10 months). In contrast, only 3–4% Pold1+/D400A Pold1+/+ time frame. Of 66 tumors arising 49 mice, 40 were epithelial origin (carcinomas), 24 mesenchymal (lymphomas sarcomas), two composite (teratomas); one-third these animals more than one tissue. Skin squamous cell carcinoma was most common tumor type, occurring 60% all 90% those surviving beyond 8 age. These data suppresses development strongly suggest unrepaired errors contribute to carcinogenesis. Mice deficient provide tractable model study mechanisms tumorigenesis initiated phenotype.