Harnessing R-loop dynamics: Challenging cancer therapy resistance

R-loops are atypical three-stranded nucleic acid structures composed of a stretch of DNA:RNA hybrids that displace the unpaired, single DNA strand, resulting in the formation of a characteristic loop structure. When properly regulated, R-loops have been demonstrated to control crucial processes related to RNA metabolism, epigenetic gene regulation, DNA damage repair, homologous recombination, and DNA replication. However, unscheduled R-loops can induce DNA damage, thus compromising genome stability. In line with these central features, cancer cells frequently exhibit deregulated R-loop metabolism. The action of oncogenes or mutant tumor suppressor genes is associated with alterations in R-loop levels, which in turn can disrupt physiological processes or drive cancer genome instability. A panel of antineoplastic drugs that interfere with R-loop prevention, resolution or processing has been shown to exacerbate R-loop-mediated genome instability, modulate immunity pathways and mediate cell death. Mechanisms of resistance to these drugs are expected to include the activation of pathways that counteract R-loop-mediated genome instability. In this review, we will discuss key regulators of R-loops in cancer cells, therapeutic strategies that promote R-loop formation and the relevance of R-loops for cancer therapy resistance.