AUTHOR=Liu Junzhe , Li Fengze , Cao Yulong , Lv Yonghui , Lei Kunjian , Tu Zewei , Gong Chuandong , Wang Haiyan , Liu Feng , Huang Kai 

TITLE=Mechanisms underlining R-loop biology and implications for human disease

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 13 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2025.1537731

DOI=10.3389/fcell.2025.1537731

ISSN=2296-634X

ABSTRACT=R-loops are three-stranded non-canonical nucleic acid structures composed of nascent RNA hybridized with the template DNA strand, leaving the non-template DNA strand displaced. These structures play crucial roles in regulating gene expression, DNA replication, and transcription processes. However, R-loops have also been increasingly described as highly deleterious, causing genomic instability and DNA damage. To maintain R-loops at a relatively safe level, complex regulatory mechanisms exist to prevent their excessive formation. The growing understanding of R-loop functions has provided valuable insights into their structure and potential clinical applications. Emerging research indicates that R-loops contribute to the pathogenesis of various disorders, including neurodegenerative, immune-related, and neoplastic diseases. This review summarizes R-loop metabolism and its significance in the etiology of associated disorders. By elucidating the regulatory mechanisms governing R-loops, we aim to establish a theoretical foundation for understanding disease pathogenesis and exploring novel therapeutic strategies targeting these hybrid nucleic acid structures.