R Loops and Their Composite Cancer Connections

R loops are three-stranded nucleic acid structures consisting of an RNA molecule that has invaded duplex DNA. R-loop structures have normal functions in regulating gene expression, class-switch recombination, telomere stability, and mitochondrial DNA replication. However, unscheduled R-loop accumulation is a driver of DNA replication stress and genome instability. Meanwhile, R loops and associated transcription-replication conflicts have been observed in cells that have lost tumor-suppressor genes or have activated oncogenes. While ectopic R loops can both disrupt epigenetic states, and promote genome instability, in most cases the hinted-at direct links between R loops and cancer development are lacking. Here, we review the possible influences of altered R-loop stability and metabolism on cancer development and discuss how R-loop accumulation might be exploited to benefit cancer patients.