The E705K mutation in hPMS2 exerts recessive, not dominant, effects on mismatch repair

Cancer Lett. 2007 May 8;249(2):148-56. doi: 10.1016/j.canlet.2006.08.008. Epub 2006 Oct 9.


The hPMS2 mutation E705K is associated with Turcot syndrome. To elucidate the pathogenesis of hPMS2-E705K, we modeled this mutation in yeast and characterized its expression and effects on mutation avoidance in mammalian cells. We found that while hPMS2-E705K (pms1-E738K in yeast) did not significantly affect hPMS2 (Pms1p in yeast) stability or interaction with MLH1, it could not complement the mutator phenotype in MMR-deficient mouse or yeast cells. Furthermore, hPMS2-E705K/pms1-E738K inhibited MMR in wild-type (WT) mammalian cell extracts or yeast cells only when present in excess amounts relative to WT PMS2. Our results strongly suggest that hPMS2-E705K is a recessive loss-of-function allele.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics*
  • Adenosine Triphosphatases / metabolism
  • Alleles
  • Animals
  • Cell Line
  • DNA Mismatch Repair
  • DNA Repair Enzymes / genetics*
  • DNA Repair Enzymes / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Genes, Dominant
  • Genes, Recessive
  • Humans
  • Mice
  • Mismatch Repair Endonuclease PMS2
  • Mutation
  • Neoplastic Syndromes, Hereditary / genetics
  • Saccharomyces cerevisiae / genetics


  • DNA-Binding Proteins
  • Adenosine Triphosphatases
  • PMS2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • DNA Repair Enzymes