title: LRF maintains genome integrity by regulating the non-homologous end joining pathway of DNA repair.
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.
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Xue-Song
authors.initials: XS
authors.lastname: Liu
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Gurushankar
authors.initials: G
authors.lastname: Chandramouly
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Emilie
authors.initials: E
authors.lastname: Rass
authors.affiliation: Department of Systems Biology, Harvard Medical School, 4 Blackfan Circle, HIM 564, Boston, MA 02115, USA.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Guocan
authors.initials: G
authors.lastname: Wang
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hobbs
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Anbazhagan
authors.initials: A
authors.lastname: Rajendran
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Anyong
authors.initials: A
authors.lastname: Xie
authors.affiliation: Department of Systems Biology, Harvard Medical School, 4 Blackfan Circle, HIM 564, Boston, MA 02115, USA.
authors.forename: Jagesh V
authors.initials: JV
authors.lastname: Shah
authors.affiliation: Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Centre, 2201 Inwood Rd, Dallas, Texas 75390, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Davis
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Scully
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lunardi
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D016678:Genome; D051379:Mice; D040081:Protein Array Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; C117093:Zbtb7a protein, mouse