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This schematic illustrates mechanisms (established in earlier work46) for non-replicative DNA-repeat expansion in post-mitotic cells. Extrahelical DNA extrusions (“slip-out” structures) form from mispairing within the CAG-repeat tract after strand separation (e.g., due to transcription). The MutSβ complex can bind to these transient structures, initiating DNA excision and resynthesis, which (when initiated on the strand opposite the slip-out) can result in the incorporation of an extra repeat unit. Occurring many times across a human lifetime, this mutational process results in a progressive expansion of the DNA repeat.

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