Mechanisms underlining R-loop biology and implications for human disease

Liu Junzhe ¹ Fengze Li ² Yulong Cao ² Yonghui Lv ¹ Kunjian Lei ¹ Zewei Tu ¹ Chuandong Gong ¹ Kai Huang ^1* Haiyan Wang ^3* Feng Liu ^4*

• ¹ Department of Neurosurgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
• ² Queen Mary college, Nanchang University, Nanchang, Jiangxi Province, China
• ³ Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
• ⁴ Department of Neurosurgery, Jiangxi Provincial Children’s Hospital, Nanchang, Jiangxi Province, China

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.