Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6.
Defects in genes associated with DNA mismatch repair (MMR) have been linked to hereditary colon cancer. Because the MMR pathway includes multiple factors with both overlapping and divergent functions, we sought to compare the impact of deficiencies in each of several MMR genes on genetic instability using a collection of knock-out mouse models. We investigated mutation frequencies and patterns in MMR-deficient mice using two transgenic reporter genes, supFG1 and cII, in the context of mice deficient for Pms2, Mlh1, Msh2, Msh3 or Msh6 or both Msh2 and Msh3 or both Msh3 and Msh6. We found that the mean mutation frequencies of all of the MMR-deficient mice were significantly higher than the mean mutation frequencies of wild-type mice. Mlh1-deficient mice and Msh2-deficient mice had the highest mutation frequencies in a comparison of the single nullizygous mice. Of all the mice studied, mice nullizygous for both Msh2 and Msh3 and those nullizygous for both Msh3 and Msh6 displayed the greatest overall increases in mutation frequencies compared with wild-type mice. Sequence analysis of the mutated reporter genes revealed significant differences between the individual groups of MMR-deficient mice. Taken together, our results further characterize the functions of the MMR factors in mutation avoidance and provide in vivo correlation to biochemical models of the MMR pathway.
Hegan
Denise Campisi
DC
Department of Therapeutic Radiology, Yale University School of Medicine, PO Box 208040, New Haven, CT 06520-8040, USA.
Narayanan
Latha
L
Jirik
Frank R
FR
Edelmann
Winfried
W
Liskay
R Michael
RM
Glazer
Peter M
PM
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics*; D003433:Crosses, Genetic; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000172:deficiency* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000172:deficiency* / Q000235:genetics; D000074081:MutS Homolog 3 Protein; D009154:Mutation; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D011506:Proteins / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501485:Mlh1 protein, mouse; C089762:Msh3 protein, mouse; D000074081:MutS Homolog 3 Protein; D009687:Nuclear Proteins; D011506:Proteins; D000251:Adenosine Triphosphatases; C499533:Pms2 protein, mouse; D000070976:Mismatch Repair Endonuclease PMS2; C497173:Msh2 protein, mouse; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes