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

doi:10.1038/ncomms9325

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 journal › Article › Research › peer-review

19 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 language	English
Article number	8325
Number of pages	10
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9325
Publication status	Published - 8 Oct 2015
Externally published	Yes

Keywords

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

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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 Kr{\"u}ppel (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.",

keywords = "cell signalling, non-homologous-end joining, transcription factors, tumour biomarkers",

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

year = "2015",

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doi = "10.1038/ncomms9325",

language = "English",

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journal = "Nature Communications",

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T1 - LRF maintains genome integrity by regulating the non-homologous end joining pathway of DNA repair

AU - Liu, Xue Song

AU - Chandramouly, Gurushankar

AU - Rass, Emilie

AU - Guan, Yinghua

AU - Wang, Guocan

AU - Hobbs, Robin M.

AU - Rajendran, Anbazhagan

AU - Xie, Anyong

AU - Shah, Jagesh V.

AU - Davis, Anthony J.

AU - Scully, Ralph

AU - Lunardi, Andrea

AU - Pandolfi, Pier Paolo

PY - 2015/10/8

Y1 - 2015/10/8

N2 - 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.

AB - 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.

KW - cell signalling

KW - non-homologous-end joining

KW - transcription factors

KW - tumour biomarkers

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DO - 10.1038/ncomms9325

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SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 8325

ER -

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

Abstract

Keywords

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