Subsequently, we have shown that loss of MMR-MutSa heterodimer Cyclic Pifithrin-alpha hydrobromide protein components, Msh2 or Msh6, leads to a significant decline in somatic GAA repeat expansions. In contrast, loss of Pms2 protein increases GAA repeat expansions in neuronal tissues, particularly the cerebellum and DRG. However, this effect is not detectable in non-neuronal tissues, which are less susceptible to FXN GAA repeat instability. Pristanic acid solution Mechanistically, MutS-heterodimers are recruited to recognize base-base mismatches or small nucleotide insertion/deletion loops during MMR function. This procedure is then continued within eukaryotes by another MMR heterodimer complex, named MutL. This heterodimer complex comprises 4 different homologues: MLH1, MLH3, PMS1 and PMS2. MLH1 plays a central role by interacting with PMS2, PMS1 or MLH3 to form the three heterodimeric complexes MutLa, MutLb and MutLc, respectively. MutLa-heterodimers can interact with both MutSa and MutSb, but MutLc is only able to interact with MutSb during the MMR process. The precise function of MutLb is not yet determined. Although several studies have revealed a crucial role for MSH2, MSH3, MSH6 and PMS2 proteins on the dynamics of trinucleotide repeat based diseases, there are limited investigations of the MLH1 protein. However, recent studies of Huntington disease HdhQ111 transgenic mice have shown that Mlh1 is required to increase the CAG repeat expansion in somatic tissues. To study the potential role of Mlh1 protein on intergenerational and somatic GAA repeat instability, we have crossed YG22 transgenic mice with mice that are deficient for Mlh1. Our findings demonstrate that Mlh1 promotes GAA repeat expansions within intergenerational transmissions and within selective somatic tissues. Moreover, to explore the effect of Pms2 or Mlh1 function on GAA repeat dynamics, we determined FXN transcription levels in tissues from MMR wild type mice compared with MMR knockout mice. Our results showed downregulation of FXN transcription associated with loss of either Pms2 or Mlh1 proteins. We also observed a similar effect in HCT-116 human cells, which are non-GAA repeat expansion cells that have loss of both MLH1 and PMS2 activities.