Non-coding RNA regulation of the radiation-induced DNA damage response and its translational relevance.

Radiotherapy outcomes are strongly influenced by the DNA damage response (DDR), a coordinated network of signalling proteins, that detects breaks in DNA, and governs DNA repair, cell cycle checkpoint activation and cell-fate decisions. While canonical DDR control has traditionally been attributed to protein kinases such as ataxia-telangiectasia mutated (ATM), ATM and rad3-related (ATR), and DNA-dependent protein kinase catalytic subunit (DNA-PKcs), accumulating evidence demonstrates that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and emerging small RNA classes, serve as important upstream regulators of these pathways. In this review, we synthesise current evidence on how ncRNAs regulate core DDR signalling networks and direct the balance between homologous recombination (HR) and non-homologous end joining (NHEJ), thereby influencing repair fidelity and overall cellular responses to radiation. We outline how ncRNAs regulate early DDR events in response to ionizing radiation, including the sensing of DNA double-strand breaks and the chromatin remodelling required for efficient recruitment of repair factors. In addition, we summarise emerging radiation-responsive RNA species such as DNA damage response RNAs (DDRNAs), vault RNAs (vtRNAs), and tRNA-derived fragments (tRFs) that contribute to genome stability and stress adaptation. Clinically, circulating ncRNAs represent minimally invasive biomarkers of radiation response, and their targeted modulation offers an opportunity for improving radiotherapy outcome, highlighting the translational relevance of defining ncRNA-mediated DDR regulation.