Figure 3

A triplex/RNA:DNA hybrid model for Friedreich ataxia (FRDA) [11, 12, 20]. Transcription through the repeat leaves the non-template purine-rich strand transiently unpaired. This strand can then fold back and interact with the duplex that has already reannealed behind the RNA polymerase (RNAP), thereby forming a triplex. Triplex formation, in turn, leaves the pyrimidine-rich strand in the second half of the repeat free to form a hybrid with the nascent RNA. This may be facilitated by the particular stability of an RNA:DNA hybrid containing a purine-rich RNA strand [76]. Evidence suggests that nucleation of this hybrid leads to unwinding of the triplex and the formation of a long persistent RNA:DNA hybrid that involves the whole repeat. The net result is the formation of a stable R loop in which the pyrimidine strand of the repeat is hybridized to the nascent transcript leaving the purine-rich strand unpaired. The RNAP becomes trapped on the template at the 3' end of the repeat.