title: Orphan receptor TR3 enhances p53 transactivation and represses DNA double-strand break repair in hepatoma cells under ionizing radiation.
abstract: In response to ionizing radiation (IR)-induced DNA double-strand breaks (DSB), cells elicit an evolutionarily conserved checkpoint response that induces cell cycle arrest and either DNA repair or apoptosis, thereby maintaining genomic stability. DNA-dependent protein kinase (DNA-PK) is a central enzyme involved in DSB repair for mammalian cells that comprises a DNA-PK catalytic subunit and the Ku protein, which act as regulatory elements. DNA-PK also functions as a signaling molecule to selectively regulate p53-dependent apoptosis in response to IR. Herein, we demonstrate that the orphan nuclear receptor TR3 suppresses DSB repair by blocking Ku80 DNA-end binding activity and promoting DNA-PK-induced p53 activity in hepatoma cells. We find that TR3 interacts with Ku80 and inhibits its binding to DNA ends, which then suppresses DSB repair. Furthermore, TR3 is a phosphorylation substrate for DNA-PK and interacts with DNA-PK catalytic subunit in a Ku80-independent manner. Phosphorylated TR3, in turn, enhances DNA-PK-induced phosphorylation and p53 transcription activity, thereby enhancing IR-induced apoptosis in hepatoma cells. Together, our findings reveal novel functions for TR3, not only in DSB repair regulation but also in IR-induced hepatoma cell apoptosis, and they suggest that TR3 is a potential target for cancer radiotherapy.
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Bi-xing
authors.initials: BX
authors.lastname: Zhao
authors.forename: Hang-zi
authors.initials: HZ
authors.lastname: Chen
authors.forename: Xiao-dan
authors.initials: XD
authors.lastname: Du
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.forename: Jian-ping
authors.initials: JP
authors.lastname: He
authors.forename: Rong-hao
authors.initials: RH
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.forename: Ru-rong
authors.initials: RR
authors.lastname: Hou
authors.forename: Ming
authors.initials: M
authors.lastname: Hong
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wu
mesh_terms: D034961:Antigens, Nuclear / Q000378:metabolism; D017209:Apoptosis / Q000528:radiation effects; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D000072200:Ku Autoantigen; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D010766:Phosphorylation / Q000528:radiation effects; D011485:Protein Binding / Q000528:radiation effects; D011839:Radiation, Ionizing; D012097:Repressor Proteins / Q000378:metabolism; D013379:Substrate Specificity / Q000528:radiation effects; D014158:Transcription, Genetic / Q000528:radiation effects; D015533:Transcriptional Activation / Q000235:genetics* / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; D009687:Nuclear Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen