NRAGE is involved in homologous recombination repair to resist the DNA-damaging chemotherapy and composes a ternary complex with RNF8-BARD1 to promote cell survival in squamous esophageal tumorigenesis.

Abstract	NRAGE, a neurotrophin receptor-interacting melanoma antigen-encoding gene homolog, is significantly increased in the nucleus of radioresistant esophageal tumor cell lines and is highly upregulated to promote cell proliferation in esophageal carcinomas (ECs). However, whether the overexpressed NRAGE promotes cell growth by participating in DNA-damage response (DDR) is still unclear. Here we show that NRAGE is required for efficient double-strand breaks (DSBs) repair via homologous recombination repair (HRR) and downregulation of NRAGE greatly sensitizes EC cells to DNA-damaging agents both in vitro and in vivo. Moreover, NRAGE not only regulates the stability of DDR factors, RNF8 and BARD1, in a ubiquitin-proteolytic pathway, but also chaperons the interaction between BARD1 and RNF8 via their RING domains to form a novel ternary complex. Additionally, the expression of NRAGE is closely correlated with RNF8 and BARD1 in esophageal tumor tissues. In summary, our findings reveal a novel function of NRAGE that will help to guide personalized esophageal cancer treatments by targeting NRAGE to increase cell sensitivity to DNA-damaging therapeutics in the long run.
Authors	Q Yang, Q Pan, C Li, Y Xu, C Wen, F Sun
Journal	Cell death and differentiation (Cell Death Differ) Vol. 23 Issue 8 Pg. 1406-16 (08 2016) ISSN: 1476-5403 [Electronic] England
PMID	27035619 (Publication Type: Journal Article)
Chemical References	Antigens, Neoplasm Antineoplastic Agents DNA-Binding Proteins H2AX protein, human Histones MAGED1 protein, human Neoplasm Proteins Neuregulins RNF8 protein, human Tumor Suppressor Proteins BARD1 protein, human Ubiquitin-Protein Ligases Cisplatin
Topics	Animals Antigens, Neoplasm (genetics, metabolism) Antineoplastic Agents (therapeutic use) Carcinoma, Squamous Cell (drug therapy, metabolism, pathology) Cell Line Cell Survival Cisplatin (therapeutic use) DNA Breaks, Double-Stranded (radiation effects) DNA Repair DNA-Binding Proteins (chemistry, metabolism) Down-Regulation Esophageal Neoplasms (drug therapy, metabolism, pathology) Histones (genetics, metabolism) Humans Mice Mice, Inbred C57BL Mice, Nude Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism) Neuregulins (antagonists & inhibitors, genetics, metabolism) Radiation, Ionizing Skin Neoplasms (etiology, pathology) Tumor Suppressor Proteins (chemistry, metabolism) Ubiquitin-Protein Ligases (chemistry, metabolism) Ultraviolet Rays

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