Liu Xue-Song, Chandramouly Gurushankar, Rass Emilie, Guan Yinghua, Wang Guocan, Hobbs Robin M, Rajendran Anbazhagan, Xie Anyong, Shah Jagesh V, Davis Anthony J, Scully Ralph, Lunardi Andrea, Pandolfi Pier Paolo
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.
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts 02215, USA.
Nat Commun. 2015 Oct 8;6:8325. doi: 10.1038/ncomms9325.
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.
白血病/淋巴瘤相关因子（LRF）是一种POZ/BTB和Krüppel（POK）转录抑制因子，其特点是在细胞命运决定和肿瘤发生中具有依赖于上下文的关键作用。在此，我们证明了LRF在双链断裂（DSB）修复的经典非同源末端连接（cNHEJ）途径中具有意想不到的非转录功能。我们发现，细胞系和小鼠组织中LRF的缺失会导致cNHEJ缺陷、基因组不稳定以及对电离辐射的超敏反应。从机制上讲，我们表明LRF在DSB上结合并稳定DNA-PKcs，进而促进DNA-PK活性。重要的是，LRF的缺失恢复了p53缺失细胞对电离辐射的敏感性，这使得LRF成为一种有吸引力的生物标志物，可根据合成致死策略，将p53缺失且LRF缺陷的肿瘤导向基于基因毒性剂或PARP抑制剂的治疗。
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