A MutS?-Dependent Contribution of MutS? to Repeat Expansions in Fragile X Premutation Mice?

ABSTRACT: The fragile X-related disorders result from expansion of a CGG/CCG microsatellite in the 5' UTR of the FMR1 gene. We have previously demonstrated that the MSH2/MSH3 complex, MutS?, that is important for mismatch repair, is essential for almost all expansions in a mouse model of these disorders. Here we show that the MSH2/MSH6 complex, MutS? also contributes to the production of both germ line and somatic expansions as evidenced by the reduction in the number of expansions observed in Msh6-/- mice. This effect is not mediated via an indirect effect of the loss of MSH6 on the level of MSH3. However, since MutS? is required for 98% of germ line expansions and almost all somatic ones, MutS? is apparently not able to efficiently substitute for MutS? in the expansion process. Using purified human proteins we demonstrate that MutS?, like MutS?, binds to substrates with loop-outs of the repeats and increases the thermal stability of the structures that they form. We also show that MutS? facilitates binding of MutS? to these loop-outs. These data suggest possible models for the contribution of MutS? to repeat expansion. In addition, we show that unlike MutS?, MutS? may also act to protect against repeat contractions in the Fmr1 gene.

SUBMITTER: Zhao XN 

PROVIDER: S-EPMC4948851 | biostudies-other | 2016 Jul

REPOSITORIES: biostudies-other