Figure 1.

A proposed model for the emerging roles of RNA DNA hybrids in C9orf72 repeat-expansion-associated diseases. Repeat-containing RNAs (red) invade DNA duplexes (blue) and form RNA•DNA hybrids, R-loops. The R-loops promote repeat instability and may in turn be influenced by variable repeat lengths. These R-loops can initiate transcriptional repression through several regulatory mechanisms, including polymerase pausing/termination, antisense transcription, and histone/DNA methylation. The formation of R-loops is closely tied to multiple aspects of RNA metabolism, including transcription, splicing, degradation, and nuclear transport. Transcripts containing the C9orf72 repeats could act locally upon the C9orf72 gene or globally at other genomic sites. Thus, R-loops may contribute to disease through reduced expression of C9orf72 gene products as well as acquired nucleic acid-based toxicity.