RNA-Mediated DNA Damage Response and Repair Mechanisms

Cells are constantly challenged by DNA lesions, of which double-strand breaks (DSBs) pose a severe threat to genomic integrity. Beyond classical protein-centric pathways, diverse RNA species have emerged as central actors in the DNA damage response (DDR). Immediately after DSB induction, damage-induced long non-coding RNAs (dilncRNAs) are transcribed at break sites, forming DNA:RNA hybrids that recruit repair factors and modulate end resection. Small non-coding DDR RNAs further amplify signalling by scaffolding mediator proteins. Nascent transcripts can template error-free repair via non-homologous end joining (NHEJ) or microhomology-mediated end joining (MMEJ), while specialised long non-coding RNAs coordinate homologous recombination (HR) through interactions with key kinases. This RNA-mediated layer of DDR influences repair pathway choice, maintains genome stability and underpins cellular resilience to genotoxic stress, with profound implications for cancer biology and therapeutic intervention.

Research from Nature Portfolio

Recent studies have demonstrated that both sense and antisense transcript RNAs directly influence DSB repair via end-joining pathways. Depending on sequence complementarity with broken DNA ends, these transcripts can promote NHEJ or MMEJ independently of DNA synthesis, revealing an RNA-guided mechanism for modulating repair fidelity and pathway choice. Foundational work has also shown that regulated DNA:RNA hybrid formation at DSBs is critical for homologous recombination. The BRCA2 protein orchestrates RNase H2 recruitment to control hybrid levels, ensuring efficient RAD51 loading and error-free repair, thus highlighting the necessity of balanced hybrid resolution for genome integrity.

RNA-Mediated DNA Damage Response and Repair Mechanisms publication trend

The graph below shows the total number of articles in rna-mediated dna damage response and repair mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Double-strand break (DSB): A lesion involving concurrent breaks in both strands of the DNA helix, posing a critical threat to genomic stability.

Non-homologous end joining (NHEJ): A repair pathway that ligates broken DNA ends with minimal sequence homology, often leading to small insertions or deletions.

Homologous recombination (HR): An error-free repair mechanism using an intact homologous sequence as a template for precise DNA synthesis at breaks.

Long non-coding RNA (lncRNA): A transcript longer than 200 nucleotides that does not encode a protein but can regulate gene expression and repair processes.

DNA:RNA hybrid: A nucleic acid structure formed when an RNA transcript anneals to complementary DNA, influencing repair factor recruitment.

R loop: A three-strand nucleic acid structure comprising an RNA:DNA hybrid and a displaced single-stranded DNA, implicated in transcription-coupled repair.

References

1. RNA-mediated double-strand break repair by end-joining mechanisms. Nature Communications (2024).
2. ATR-binding lncRNA ScaRNA2 promotes cancer resistance through facilitating efficient DNA end resection during homologous recombination repair. Journal of Experimental & Clinical Cancer Research (2023).
3. BRCA2 controls DNA:RNA hybrid level at DSBs by mediating RNase H2 recruitment. Nature Communications (2018).
4. A damaged genome’s transcriptional landscape through multilayered expression profiling around in situ-mapped DNA double-strand breaks. Nature Communications (2017).
5. DICER, DROSHA and DNA damage response RNAs are necessary for the secondary recruitment of DNA damage response factors. Journal of Cell Science (2016).
6. Tyrosine kinase c-Abl couples RNA polymerase II transcription to DNA double-strand breaks. Nucleic Acids Research (2019).