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- W1980462742 abstract "We tested the ability of recombinant hMutSα (hMSH2/hMSH6) and hMutSβ (hMSH2/hMSH3) heterodimers to complement the mismatch repair defect of HEC59, a human cancer cell line whose extracts lack all three MutS homologues. Although repair of both base/base mispairs and insertion–deletion loops was restored by hMutSα, only the latter substrates were addressed in extracts supplemented with hMutSβ. hMutSα was also able to complement a defect in the repair of base/base mispairs in CHO R and HL60R cell extracts. In these cells, methotrexate-induced amplification of the dihydrofolate reductase ( DHFR ) locus, which also contains the MSH3 gene, led to an overexpression of MSH3 and thus to a dramatic change in the relative levels of MutSα and MutSβ. As a rule, MSH2 is primarily complexed with MSH6. MutSα is thus relatively abundant in mammalian cell extracts, whereas MutSβ levels are generally low. In contrast, in cells that overexpress MSH3, the available MSH2 protein is sequestered predominantly into MutSβ. This leads to degradation of the partnerless MSH6 and depletion of MutSα. CHO R and HL60R cells therefore lack correction of base/base mispairs, whereas loop repair is maintained by MutSβ. Consequently, frameshift mutations in CHO R are rare, whereas transitions and transversions are acquired at a rate two orders of magnitude above background. Our data thus support and extend the findings of Drummond et al. [Drummond, J. T., Genschel, J., Wolf, E. & Modrich, P. (1997) Proc. Natl. Acad. Sci. USA 94, 10144–10149] and demonstrate that mismatch repair deficiency can arise not only through mutation or transcriptional silencing of a mismatch repair gene, but also as a result of imbalance in the relative amounts of the MSH3 and MSH6 proteins." @default.
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- W1980462742 date "1998-07-21" @default.
- W1980462742 modified "2023-10-13" @default.
- W1980462742 title "Mismatch repair deficiency associated with overexpression of the <i>MSH3</i> gene" @default.
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- W1980462742 doi "https://doi.org/10.1073/pnas.95.15.8568" @default.
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