Fragile X-associated disorders are Repeat Expansion Diseases that result from 
expansion of a CGG/CCG-repeat in the FMR1 gene. Contractions of the repeat tract 
also occur, albeit at lower frequency. However, these contractions can 
potentially modulate disease symptoms or generate an allele with repeat numbers 
in the normal range. Little is known about the expansion mechanism and even less 
about contractions. We have previously demonstrated that the mismatch repair 
(MMR) protein MSH2 is required for expansions in a mouse model of these 
disorders. Here, we show that MSH3, the MSH2-binding partner in the MutSβ 
complex, is required for 98% of germ line expansions and all somatic expansions 
in this model. In addition, we provide evidence for two different contraction 
mechanisms that operate in the mouse model, a MutSβ-independent one that 
generates small contractions and a MutSβ-dependent one that generates larger 
ones. We also show that MutSβ complexes formed with the repeats have altered 
kinetics of ATP hydrolysis relative to complexes with bona fide MMR substrates 
and that MutSβ increases the stability of the CCG-hairpins at physiological 
temperatures. These data may have important implications for our understanding 
of the mechanism(s) of repeat instability and for the role of MMR proteins in 
this process.