R loops: new modulators of genome dynamics and function

R loops form when a transcript hybridizes to a complementary DNA locus to result in an RNA–DNA hybrid and a displaced single DNA strand. Such structures can have detrimental cellular roles by causing genome instability. However, recent studies have provided detailed views of genome-wide R-loop occurrences and uncovered various apparently beneficial roles in gene regulation. This Review discusses our latest understanding of the contrasting functions of R loops and the implications for genome regulation and various diseases. R loops are nucleic acid structures composed of an RNA–DNA hybrid and a displaced single-stranded DNA. Recently, evidence has emerged that R loops occur more often in the genome and have greater physiological relevance, including roles in transcription and chromatin structure, than was previously predicted. Importantly, however, R loops are also a major threat to genome stability. For this reason, several DNA and RNA metabolism factors prevent R-loop formation in cells. Dysfunction of these factors causes R-loop accumulation, which leads to replication stress, genome instability, chromatin alterations or gene silencing, phenomena that are frequently associated with cancer and a number of genetic diseases. We review the current knowledge of the mechanisms controlling R loops and their putative relationship with disease.