R Loops and Their Composite Cancer Connections

R loops form in genomic DNA as part of normal transcription where they serve regulatory functions in numerous DNA and chromatin transactions. Dysregulation of R-loop metabolism impairs genome maintenance, replicative senescence, and epigenetic stability. DNA: RNA hybrids have potential regulatory roles in double-strand break repair. Mutations in many oncogenes and tumor suppressor genes disrupt R-loop occupancy and clearance from the genome. Chemotherapies can induce R loops, while R loops can modulate cellular responses to such therapies. 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. 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.