RNA–DNA hybrids are generated during transcription, DNA replication and DNA repair and are crucial intermediates in these processes. When RNA–DNA hybrids are stably formed in double-stranded DNA, they displace one of the DNA strands and give rise to a three-stranded structure called an R-loop. R-loops are widespread in the genome and are enriched at active genes. R-loops have important roles in regulating gene expression and chromatin structure, but they also pose a threat to genomic stability, especially during DNA replication. To keep the genome stable, cells have evolved a slew of mechanisms to prevent aberrant R-loop accumulation. Although R-loops can cause DNA damage, they are also induced by DNA damage and act as key intermediates in DNA repair such as in transcription-coupled repair and RNA-templated DNA break repair. When the regulation of R-loops goes awry, pathological R-loops accumulate, which contributes to diseases such as neurodegeneration and cancer. In this Review, we discuss the current understanding of the sources of R-loops and RNA–DNA hybrids, mechanisms that suppress and resolve these structures, the impact of these structures on DNA repair and genome stability, and opportunities to therapeutically target pathological R-loops.

RNA-DNA 杂交体在转录、DNA 复制和 DNA 修复过程中产生，是这些过程中的关键中间体。当 RNA-DNA 杂交体在双链 DNA 中稳定形成时，它们会取代其中一条 DNA 链并产生称为 R 环的三链结构。R-loops 在基因组中广泛存在，并在活性基因处富集。R 环在调节基因表达和染色质结构方面具有重要作用，但它们也会对基因组稳定性构成威胁，尤其是在 DNA 复制期间。为了保持基因组稳定，细胞已经进化出一系列机制来防止异常的 R 环积累。尽管 R-loops 可引起 DNA 损伤，但它们也会由 DNA 损伤诱导，并作为 DNA 修复的关键中间体，例如转录偶联修复和 RNA 模板 DNA 断裂修复。当 R-loops 的调节出现问题时，病理性 R-loops 就会积累，从而导致神经退行性疾病和癌症等疾病。在这篇综述中，我们讨论了目前对 R 环和 RNA-DNA 杂交体来源的理解、抑制和解决这些结构的机制、这些结构对 DNA 修复和基因组稳定性的影响，以及治疗靶向病理 R- 的机会循环。