The Yin and Yang of R-loop biology

Abstract

RNA performs diverse functions in cells, directing translation, modulating transcription and catalyzing enzymatic reactions. Remarkably RNA can also anneal to its genomic template co- or post-transcriptionally to generate an RNA-DNA hybrid and a displaced single-stranded DNA. These unusual nucleic acid structures are called R-loops. Studies in the last decades concentrated on the detrimental effects of R-loop formation, particularly on genome stability. In fact, R-loops are thought to play a role in several human diseases like cancer and neurodegenerative syndromes. But recent data has revealed that R-loops can also have a positive impact on cell processes, like regulating gene expression, chromosome structure and DNA repair. Here we summarize our current understanding of the formation and dissolution of R-loops, and discuss their negative and positive impact on genome structure and function.

Figure 1. R-loop formation and dissolution

The R-loop can form co-transcriptionally (in cis) or post-transcriptionally (in trans), a process mediated by Rad51. R-loop formation is elevated by defects in RNA processing factors that coat, splice, export and degrade the nascent RNA. R-loop dissolution is promoted by RNase H enzymes that recognize and degrade the RNA in the R-loop, and by RNA-DNA helicases that unwind the RNA molecule.

Figure 2. The Yin and Yang of R-loop Biology

R-loop formation can have a detrimental impact on the genome stability, but also contributes positively in regulating cellular processes. Several factors can contribute to R-loop mediated genomic instability: exposure of unstable ssDNA, proteins that modify the ssDNA, R-loop interference with the transcription and replication machinery. On the other side, R-loops can contribute to efficiently terminate transcription, recruit epigenetic regulators to modulate gene expression and chromosome compaction, contribute to DNA repair and regulate transcription of specific genes.