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 Krueppel (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 instability and hypersensitivity to ionizing radiation. Mechanistically, we show that LRF binds and stabilizes DNA-PKcs on DSBs, in turn favouring DNA-PK activity. Importantly, LRF loss restores ionizing radiation sensitivity 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 inhibitors following a synthetic lethal strategy.
Mesh Terms:
Animals, Cells, Cultured, DNA Repair, DNA-Binding Proteins, Fibroblasts, Gene Expression Regulation, Genome, Mice, Protein Array Analysis, Transcription Factors
Animals, Cells, Cultured, DNA Repair, DNA-Binding Proteins, Fibroblasts, Gene Expression Regulation, Genome, Mice, Protein Array Analysis, Transcription Factors
Nat Commun
Date: Oct. 08, 2015
PubMed ID: 26446488
View in: Pubmed Google Scholar
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