Fig. 5.
Proposed mechanism for stable RNA·DNA hybrids stimulating repeat instability. Transcription of DNA regions containing a CG-rich trinucleotide repeat (shown in red) favors formation of stable RNA·DNA hybrids. The nontemplate DNA strand, which is displaced and rendered single-stranded (unpaired), can adopt non-B DNA structures such as CTG or CAG hairpins. The unpaired regions of the nontemplate strand are susceptible to bisulfite modification. These non-B DNA structures may be recognized directly by cellular DNA repair processes such as transcription-coupled repair, nucleotide excision repair, mismatch repair, or they may lead to formation of double-stranded DNA breaks. Alternatively, if the RNA (shown in yellow) is ultimately removed from the R loop, the template strand could re-pair with the nontemplate strand to generate a slipped duplex (37), which then engages a DNA repair process. We propose that repeat instability is a consequence of the repair process that are called into play by the non-B DNA structures whose formation is enhanced by transcriptional R loops.