LRF maintains genome integrity by regulating the non-homologous end joining pathway of DNA repair

Leukemia/lymphoma-related factor (LRF) is a POZ/BTB and Kruppel(POK) transcriptional repressor characterized by context-dependent key roles in cell fate decision and tumorigenesis. Here we demonstrate an unexpected transcription-independent function for LRF in the classical non-homologous end joining(cNHEJ) pathway of double-strand break (DSB) repair. We find that LRF loss in cell lines and mouse tissues results in defective cNHEJ, genomic instabilityand hypersensitivity to ionizing radiation. Mechanistically, we show that LRF binds and stabilizes DNA-PKcson DSBs, in turn favouring DNA-PK activity. Importantly, LRF loss restores ionizing radiationsensitivity to p53 null cells, making LRF an attractive biomarker to direct p53-null LRF-deficient tumours towards therapeutic treatments based on genotoxic agents or PARP inhibitorsfollowing a synthetic lethalstrategy.