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

Xue Song Liu, Gurushankar Chandramouly, Emilie Rass, Yinghua Guan, Guocan Wang, Robin M. Hobbs, Anbazhagan Rajendran, Anyong Xie, Jagesh V. Shah, Anthony J. Davis, Ralph Scully, Andrea Lunardi, Pier Paolo Pandolfi

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11 Citations (Scopus)

Abstract

Leukemia/lymphoma-related factor (LRF) is a POZ/BTB and Krüppel (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.

Original languageEnglish
Article number8325
Number of pages10
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 8 Oct 2015
Externally publishedYes

Keywords

  • cell signalling
  • non-homologous-end joining
  • transcription factors
  • tumour biomarkers

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