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Replication dependent and independent mechanisms of GAA repeat instability

(GAA)n repeat instability arises during both replication-dependent processes, such as cell division and intergenerational transmission, as well as in terminally differentiated somatic tissues. Here, the authors provide a brief historical overview on the discovery of (GAA)n repeat expansions and their association to FRDA, followed by recent advances in the identification of triplex H-DNA formation and replication fork stalling. The main body of this review focuses on the last decade of progress in understanding the mechanism of (GAA)n repeat instability during DNA replication and/or DNA repair. The Authors propose that the discovery of additional mechanisms of (GAA)n repeat instability can be achieved via both comparative approaches to other repeat expansion diseases and genome-wide association studies. Finally, advances towards FRDA prevention or amelioration that specifically target (GAA)n repeat expansions are discussed.

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