The relevance of RNA-DNA interactions as regulators of physiological functions

RNA-DNA interactions are fundamental to cellular physiology, playing critical roles in genome integrity, gene expression, and stress responses. This review highlights the diverse structures of RNA-DNA hybrids, including R-loops, RNA-DNA triplexes, and RNA-DNA hybrid G-quadruplexes (hG4s) and their relevance in physiology. R-loops are formed during transcription and replication, which regulate gene expression and chromatin dynamics but can also threaten genome stability. RNA-DNA triplexes, often formed by long noncoding RNAs (lncRNAs) such as FENDRR and MEG3, recruit chromatin modifiers like Polycomb repressive complex 2 to modulate gene expression, influencing organogenesis and cell specification. hG4s, formed by guanine-rich sequences in RNA and DNA, regulate transcription termination and telomere stability. Through this, hG4s can affect gene suppression and replication regulation. RNA-DNA hybrids are tightly regulated by helicases, RNase H enzymes, and topoisomerases, with altered regulation linked to genomic instability and disease. This review discusses the complexity of RNA-DNA interactions and their recently identified contributions to cellular physiology.