R-loops and D-loops: a delicate balance in genomic stability and instability

Cell Communication and Signaling

卷:24

Review

Zhendong Qin¹  Mingjun Lu¹  Jiaqi Zhao¹  Jiabao Hou¹  Jingwei Guo¹  Jinghong Wu¹  Chenyang Wang¹  Xiaoyue Zhu¹  Teng Ma¹ 

[1] Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, 101149, Beijing, China

关键词: R-loop;    D-loop;    Genome stability;    DNA replication;    Transcription;    Homologous recombination;   

DOI  :  10.1186/s12964-026-03033-5

 received in 2026-03-29, accepted in 2026-06-24,  发布年份 2026

来源: Springer

【 摘 要 】

R-loops and D-loops are three-stranded nucleic acid structures that have emerged as central regulators of genome stability, gene expression, and DNA metabolism. R-loops form co-transcriptionally or post-transcriptionally when nascent RNA re-anneals with the template DNA strand, generating an RNA: DNA hybrid that displaces the non-template strand into a single-stranded state. These structures are enriched at CpG island promoters, transcription termination sites, and immunoglobulin class-switch regions, where they coordinate transcription regulation, chromatin remodeling, and DNA damage signaling. D-loops are formed when a single-stranded DNA segment pairs with one strand of a duplex and displaces the other, arising through context-dependent mechanisms that include RAD51- or DMC1-mediated strand invasion in homologous recombination, shelterin-assisted invasion at telomeres, and replication-coupled strand displacement at the mitochondrial DNA origin. They serve as indispensable intermediates in double-strand break repair, telomere maintenance, and mitochondrial DNA replication. Recent cryo-electron microscopy studies have resolved the stepwise RAD51-mediated strand exchange mechanism at near-atomic resolution, substantially advancing structural understanding of D-loop biogenesis. Despite their differences in molecular composition, both structures remodel Watson-Crick base pairing and, when dysregulated, are associated with replication fork stalling, transcription-replication conflicts, and aberrant recombination. This review systematically compares the structural features, formation mechanisms, regulatory networks, and biological functions of R-loops and D-loops, with emphasis on their convergent roles in safeguarding genome integrity. We further discuss rapidly evolving detection technologies and emerging therapeutic strategies targeting these structures in cancer and neurodegeneration, identifying key unresolved questions for future investigation.

【 授权许可】

CC BY   
© The Author(s) 2026

【 图 表 】

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