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

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 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.

Polymerases:

Topics:

Status:

new topics/pols set partial results complete validated

Results:

No results available for this paper.

Entry validated by:

Log in to edit reference All References

Using Polbase tables:

Sorting:

Tables may be sorted by clicking on any of the column titles. A second click reverses the sort order. <Ctrl> + click on the column titles to sort by more than one column (e.g. family then name).

Filtering:

It is also possible to filter the table by typing into the search box above the table. This will instantly hide lines from the table that do not contain your search text.