Proposed model of MutS and MutL-dependent events leading to CAG•CTG somatic instability.

CAG•CTG repeat structures are initially recognized by the MutSβ (MSH2-MSH3) complex [25], [98]. The loop in the CAG•CTG repeat tract represents a short slip-out, previously identified as the main substrate for MMR protein-dependent repair of CAG•CTG structures in cell free systems [50], [51]. However, the nature of the putative CAG•CTG structure(s) that leads to MutS and MutL-dependent somatic instability in vivo is unknown. Following ATP hydrolysis by DNA-bound MutSβ [27], a MutLγ (MLH1–MLH3) heterodimer is preferentially recruited to the complex (thick arrow) over the MutLα (MLH1-PMS2) heterodimer (thin arrow). The total absence of HTT CAG expansion in Mlh3−/− mice suggests that PMS2 plays no role at all in this process. However, PMS2 has been shown to play a role in the expansion of CTG repeats in a DM1 mouse model [24], suggesting that these events may be genetic locus and/or mouse strain dependent. Following MutLγ binding, various pathways, e.g. canonical mismatch repair (MMR), noncanonical mismatch repair (ncMMR) and/or other DNA repair processes may be engaged and process the repeats such that they ultimately undergo expansion. Other members of alternative DNA repair pathways, namely OGG1, XPA and NEIL1 have been directly implicated in CAG/CTG somatic instability in mice [76]–[78], however, how these proteins intersect with MMR protein-dependent pathways has yet to be demonstrated.