R-loops and small RNA regulatory interactions: mechanisms and clinical perspectives

An R-loop is a three-stranded nucleic acid structure that serves as a transcriptional intermediate, consisting of an RNA-DNA hybrid and a displaced single-stranded DNA (ssDNA). Small RNAs are RNA molecules shorter than 300 nucleotides that perform a wide range of essential functions within cells. Both R-loops and small RNAs are widely present in the genomes of prokaryotes and eukaryotes, where they play crucial roles in regulating gene expression, maintaining genomic stability, and facilitating DNA damage repair. Aberrant formation and accumulation of R-loops, coupled with dysregulation of small RNA pathways, can induce DNA damage and genomic instability, ultimately contributing to cellular senescence or cell death. Here, we discuss recent advances in understanding the crosstalk between R-loops and small RNAs, with a focus on their synergistic roles in maintaining genome stability and their therapeutic potential in oncology and neurodegeneration. We propose a novel model integrating R-loop dynamics with small RNA-mediated epigenetic regulation, supported by emerging clinical trial data.