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The Distinct Spectra of Tumor-associated Apc Mutations in Mismatch Repair-deficient Apc^1638N Mice Define the Roles of MSH3 and MSH6 in DNA Repair and Intestinal Tumorigenesis¹

Strang Cancer Research Laboratory at The Rockefeller University, New York, New York 10021 [M. K., K. Y., K. F., M. L., A. M. C. B.]; Department of Cell Biology and Anatomy, Weill Medical College of Cornell University, New York, New York 10021 [A. M. C. B.]; Departments of Cell Biology [E. W., E. A., W. E.] and Molecular Genetics [R. K.], Albert Einstein College of Medicine, Bronx, New York 10461; and Ludwig Institute for Cancer Research, La Jolla, California 92093 [R. D. K.]

In mammalian cells, mismatch recognition has been attributed to two partially redundant heterodimeric protein complexes of MutS homologues, MSH2-MSH3 and MSH2-MSH6. We have conducted a comparative analysis of Msh3 and Msh6 deficiency in mouse intestinal tumorigenesis by generating Apc^1638N mice deficient in Msh3, Msh6 or both. We have found that Apc^1638N mice defective in Msh6 show reduced survival and a 6–7-fold increase in intestinal tumor multiplicity. In contrast, Msh3-deficient Apc^1638N mice showed no difference in survival and intestinal tumor multiplicity as compared with Apc^1638N mice. However, when Msh3 deficiency is combined with Msh6 deficiency (Msh3^-/-Msh6^-/-Apc^1638N), the survival rate of the mice was further reduced compared to Msh6^-/-Apc^1638N mice because of a high multiplicity of intestinal tumors at a younger age. Almost 90% of the intestinal tumors from both Msh6^-/-Apc^1638N and Msh3^-/-Msh6^-/-Apc^1638N mice contained truncation mutations in the wild-type Apc allele. Apc mutations in Msh6^-/-Apc^1638N mice consisted predominantly of base substitutions (93%) creating stop codons, consistent with a major role for Msh6 in the repair of base-base mismatches. However, in Msh3^-/-Msh6^-/-Apc^1638N tumors, we observed a mixture of base substitutions (46%) and frameshifts (54%), indicating that in Msh6^-/-Apc^1638N mice frameshift mutations in the Apc gene were suppressed by Msh3. Interestingly, all except one of the Apc mutations detected in mismatch repair-deficient intestinal tumors were located upstream of the third 20-amino acid ß-catenin binding repeat and before all of the Ser-Ala-Met-Pro repeats, suggesting that there is selection for loss of multiple domains involved in ß-catenin regulation. Our analysis therefore has revealed distinct mutational spectra and clarified the roles of Msh3 and Msh6 in DNA repair and intestinal tumorigenesis.

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