The E705K mutation in hPMS2 exerts recessive, not dominant, effects on mismatch repair.
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.
Deschênes
Suzanne M
SM
Department of Biology, Sacred Heart University, 5151 Park Ave., Fairfield, CT 06825, USA. descheness@sacredheart.edu
Tomer
Guy
G
Nguyen
Megan
M
Erdeniz
Naz
N
Juba
Nicole C
NC
Sepúlveda
Natalia
N
Pisani
Jenna E
JE
Liskay
R Michael
RM
D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D000818:Animals; D002460:Cell Line; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005799:Genes, Dominant; D005808:Genes, Recessive; D006801:Humans; D051379:Mice; D000070976:Mismatch Repair Endonuclease PMS2; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics
D004268:DNA-Binding Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes