R-Loops Play Dual Role in Genome Stability and Disease

This new review article highlights the pivotal and paradoxical role of R-loops in maintaining genomic stability while simultaneously posing risks to it. These three-stranded nucleic acid structures, composed of an RNA:DNA hybrid and a displaced DNA strand, are now recognized not merely as byproducts of transcription but as essential regulatory elements in gene expression, DNA replication, and repair mechanisms.
Genome Stability and Disease: This new review article highlights the pivotal and paradoxical role of R-loops in maintaining genomic stability while simultaneously posing risks to it. [Pixabay]
Genome Stability and Disease: This new review article highlights the pivotal and paradoxical role of R-loops in maintaining genomic stability while simultaneously posing risks to it. [Pixabay]
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Genome Stability and Disease: This new review article highlights the pivotal and paradoxical role of R-loops in maintaining genomic stability while simultaneously posing risks to it. These three-stranded nucleic acid structures, composed of an RNA:DNA hybrid and a displaced DNA strand, are now recognized not merely as byproducts of transcription but as essential regulatory elements in gene expressionDNA replication, and repair mechanisms.

The article traces the evolution of R-loop research, illuminating how sophisticated detection techniques have transformed our understanding of their biological functions. From early antibody-based imaging to high-throughput sequencing methods like DRIP-seq and R-ChIP, the field has advanced rapidly. These tools have revealed the extensive presence of R-loops at key genomic regions such as promotersterminators, and double-strand break (DSB) sites, positioning them as significant actors in the DNA damage response.

A central focus of the article is the dual nature of R-loops. Under controlled conditions, they play protective roles—regulating gene activity, terminating transcription, and facilitating repair through homologous recombination. However, when dysregulated, R-loops become hazardous. They can obstruct replication forks, induce transcription-replication collisions, and provoke DSBs, ultimately threatening genome integrity. These pathological consequences are amplified in the context of mutations in repair-related genes like BRCA1 and BRCA2, underlining their relevance in diseases such as cancer and neurodegeneration.

The article draws attention to the influence of non-coding RNAs, including lncRNAscircRNAs, and enhancer RNAs, in modulating R-loop formation. These RNA species can either stabilize or destabilize R-loops, thus influencing chromatin structure and transcriptional dynamics. Additionally, the interplay between R-loops and RNA modifications like m6A and m5C further adds to the complexity of their biological impact, especially in DNA repair pathways.

The emerging connection between R-loops and immune responses are also explored, showing how they can activate pathways like cGAS-STING, linking genomic surveillance to inflammatory signaling. This cross-disciplinary significance makes R-loops a promising frontier for therapeutic intervention, especially in diseases driven by genome instability. AlphaGalileo/SP

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