title: 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.affiliation: Department of Clinical Laboratory Medicine, Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Yang
authors.affiliation: The Central Laboratory, Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Clinical Laboratory Medicine, Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Nanjing Normal University, Nanjing 210023, China.
authors.forename: C
authors.initials: C
authors.lastname: Wen
authors.affiliation: Department of Clinical Laboratory Medicine, Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: F
authors.initials: F
authors.lastname: Sun
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival; D002945:Cisplatin / Q000627:therapeutic use; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020880:Neuregulins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing; D012878:Skin Neoplasms / Q000209:etiology / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; C120897:MAGED1 protein, human; D009363:Neoplasm Proteins; D020880:Neuregulins; C486521:RNF8 protein, human; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; D002945:Cisplatin