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

Content Provider	PubMed Central
Author	Goldsby, Robert E. Hays, Laura E. Chen, Xin Olmsted, Elise A. Slayton, William B. Spangrude, Gerry J. Preston, Bradley D.
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.
Related Links	http://dx.doi.org/10.1073/pnas.232340999
Ending Page	15565
Page Count	6
Starting Page	15560
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	24
Volume Number	99
Language	English
Publisher	National Academy of Sciences
Publisher Date	2002-11-26
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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