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

Research output: Contribution to journalArticle

10 Scopus citations

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 (US)
Article number8325
JournalNature communications
Volume6
DOIs
StatePublished - Oct 8 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Liu, X. S., Chandramouly, G., Rass, E., Guan, Y., Wang, G., Hobbs, R. M., Rajendran, A., Xie, A., Shah, J. V., Davis, A. J., Scully, R., Lunardi, A., & Pandolfi, P. P. (2015). LRF maintains genome integrity by regulating the non-homologous end joining pathway of DNA repair. Nature communications, 6, [8325]. https://doi.org/10.1038/ncomms9325