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

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 beta, 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 alpha 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 beta is required for 98% of germ line expansions and almost all somatic ones, MutS alpha is apparently not able to efficiently substitute for MutS beta in the expansion process. Using purified human proteins we demonstrate that MutS alpha, like MutS beta, 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 alpha facilitates binding of MutS beta to these loop-outs. These data suggest possible models for the contribution of MutS alpha to repeat expansion. In addition, we show that unlike MutS beta, MutS alpha may also act to protect against repeat contractions in the Fmr1 gene.