| Gene-specific repeat expansions are the cause of a growing list of neurological diseases, including myotonic dystrophy type 1 and Huntington's disease. The formation of slipped-DNA structures in the expanded repeat sequences is thought to drive repeat instability and pathogenesis by impairing normal DNA metabolic processes. Here I show that slipped-DNAs with nicks located within the repeat tract displayed increased structural heterogeneity relative to slipped-DNAs with nicks located in the flanking sequence. Nick-in-repeat slipped-DNAs were repaired better than nick-in-flank slipped-DNAs, likely due to increased amounts of single-stranded DNA at the nicked repeat ends allowing for better repair factor binding. Single-stranded DNA binding proteins RPA and aRPA seem to play an important part in tissue-specific instability as both complexes are overexpressed in the brains of HD patients. Neither RPA nor aRPA was required for slipped-DNA repair, although they both enhanced slipped-DNA repair efficiency. |
