Targeting R-loops: diverse RNA helicases in R-loop resolution and their potential as targets for cancer therapy

RNA helicases are enzymes that remodel RNA secondary structures and RNA-protein complexes using ATP-driven motor forces. They are known to participate in many essential cellular processes, including transcription, splicing, translation, RNA decay, and ribosome assembly. However, the functional diversity of RNA helicases and the multitude of associated cofactors make it difficult to grasp the full picture of their roles in these processes. Here, we focus exclusively on the R-loop-unwinding activities of RNA helicases and the cofactors involved in this process. R-loops are three-stranded nucleic acid structures that are mainly formed during transcription between newly synthesized mRNA and its template DNA. Timely resolution of R-loops by RNA helicases is required to prevent the DNA damage and replication stress that can result from collisions between transcription and DNA replication machinery acting aberrantly on the same DNA strand. Although R-loop resolution is critical for genome stability and cell proliferation, our understanding of the responsible helicases and their mechanisms remains incomplete. In this review, we summarize recent findings on R-loop-resolving helicases, discuss key questions and approaches for future investigation, and consider the potential of targeting these helicases for cancer therapy.