Recurrent DNA nicks drive massive expansions of (GAA)_n repeats.

ABSTRACT: Over 50 hereditary degenerative disorders are caused by expansions of short tandem DNA repeats (STRs). (GAA)_n repeat expansions are responsible for Friedreich's ataxia as well as late-onset cerebellar ataxias (LOCAs). Thus, the mechanisms of (GAA)_n repeat expansions attract broad scientific attention. To investigate the role of DNA nicks in this process, we utilized a CRISPR-Cas9 nickase system to introduce targeted nicks adjacent to the (GAA)_n repeat tract. We found that DNA nicks 5' of the (GAA)₁₀₀ run led to a dramatic increase in both the rate and scale of its expansion in dividing cells. Strikingly, they also promoted large-scale expansions of carrier- and large normal-size (GAA)_n repeats, recreating, in a model system, the expans

SUBMITTER: Li L 

PROVIDER: S-EPMC11626148 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature