Replication dependent and independent mechanisms of GAA repeat instability

Trinucleotide repeat instability is a driver of human disease. Large expansions of (GAA)_n repeats in the first intron of the FXN gene are the cause Friedreich’s ataxia (FRDA), a progressive degenerative disorder which cannot yet be prevented or treated. (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, we 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. We 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, we discuss the advances towards FRDA prevention or amelioration that specifically target (GAA)_n repeat expansions.