High incidence of epithelial cancers in mice deficient for DNA polymerase delta proofreading.
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 delta (poldelta, encoded by the Pold1 gene). We show that this mutation inactivates the 3' --> 5' exonuclease of poldelta 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 poldelta proofreading suppresses spontaneous tumor development and strongly suggest that unrepaired DNA polymerase errors contribute to carcinogenesis. Mice deficient in poldelta proofreading provide a tractable model to study mechanisms of epithelial tumorigenesis initiated by a mutator phenotype.
Goldsby
Robert E
RE
Eccles Institute of Human Genetics and Department of Pediatrics (Division of Pediatric HematologyOncology), University of Utah School of Medicine, Salt Lake City 84112, USA.
Hays
Laura E
LE
Chen
Xin
X
Olmsted
Elise A
EA
Slayton
William B
WB
Spangrude
Gerry J
GJ
Preston
Bradley D
BD
D000595:Amino Acid Sequence; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D002678:Chimera / Q000235:genetics; D003062:Codon / Q000235:genetics; D004258:DNA Polymerase III / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009374:Neoplasms, Experimental / Q000235:genetics*; D017354:Point Mutation; D012878:Skin Neoplasms / Q000235:genetics
D003062:Codon; D004258:DNA Polymerase III