Proteasome inhibition rescues clinically significant unstable variants of the mismatch repair protein Msh2.

ABSTRACT: MSH2 is required for DNA mismatch repair recognition in eukaryotes. Deleterious mutations in human MSH2 account for approximately half of the alleles associated with a common hereditary cancer syndrome. Previously, we characterized clinically identified MSH2 missense mutations, using yeast as a model system, and found that the most common cause of defective DNA mismatch repair was low levels of the variant Msh2 proteins. Here, we show that increased protein turnover is responsible for the reduced cellular levels. Increasing gene dosage of more than half of the missense alleles fully restored function. A titration experiment revealed that raising the expression level of one variant to less than wild-type levels restored mismatch repair, suggesting that overexpression is not always required

SUBMITTER: Arlow T 

PROVIDER: S-EPMC3538226 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature