Figure 2.

Diagrammatic representation of possible transcription-related, MMR-dependent events that could give rise to repeat expansions. As illustrated on the left-hand side of this figure, R-loops could give rise to expansions because single stranded regions of the R-loop would be prone to oxidative damage. Repair of this damage by BER would create an opportunity for strand slippage and strand-displacement that could result in the formation of hairpins or loop-outs on one or both strands [83]. Alternatively, as illustrated on the right, hairpin formation might occur on the non-template strand of the R-loop, forming an S-loop. This might favor formation of a hairpin on the template strand after dissociation of the transcript. Hairpins or double loop-outs formed by either process could then be bound by both MutS proteins. This results in the recruitment of MutLα, MutLβ, and MutLγ. MutLγ cleavage of the strands opposite each loop-out would generate a DSB that would then be repaired by some, as yet unknown, non-homologous end-joining-independent DSBR pathway.