Mechanistic roles of long non-coding RNAs in DNA damage response and genome stability

To maintain genomic stability, cells have evolved complex mechanisms collectively known as the DNA damage response (DDR), which includes DNA repair, cell cycle checkpoints, apoptosis, and gene expression regulation. Recent studies have revealed that long non-coding RNAs (lncRNAs) are pivotal regulators of the DDR. Beyond their established roles in recruiting repair proteins and modulating gene expression, emerging evidence highlights two particularly intriguing functions. First, some lncRNAs contain small open reading frames (sORFs) encoding functional micropeptides that actively participate in DDR pathways. Second, lncRNAs regulate R-loop homeostasis, a key mechanism for preserving genome integrity. Together, these findings expand our understanding of lncRNAs in the DDR, positioning them as both key mechanistic players and promising therapeutic targets.