Regulation of R-Loop Dynamics by Proteins and Long Noncoding RNAs: An Emerging Paradigm for Cancer Treatment

R-loops are three-stranded nucleic acid structures comprising an RNA/DNA hybrid and a displaced single-stranded DNA. While transient R-loop formation is essential for various physiological processes, their persistent accumulation leads to genomic instability. Cancer cells exhibit elevated R-loop levels due to hypertranscription, replication stress, and impaired DNA repair pathways. In this review, we provide a comprehensive overview of the molecular machinery that resolves R-loops, including chromatin remodelers, transcriptional regulators, nucleases, and helicases. We also highlight the emerging roles of long noncoding RNAs (lncRNAs) in modulating R-loop dynamics and explore how these RNA-based mechanisms cooperate with canonical resolution pathways. Finally, we explore the potential of targeting R-loop regulatory networks as a novel therapeutic strategy in cancer treatment.