title: Role of the translationally controlled tumor protein in DNA damage sensing and repair.
abstract: The translationally controlled tumor protein (TCTP) is essential for survival by mechanisms that as yet are incompletely defined. Here we describe an important role of TCTP in response to DNA damage. Upon exposure of normal human cells to low-dose γ rays, the TCTP protein level was greatly increased, with a significant enrichment in nuclei. TCTP up-regulation occurred in a manner dependent on ataxia-telangiectasia mutated (ATM) kinase and the DNA-dependent protein kinase and was associated with protective effects against DNA damage. In chromatin of irradiated cells, coimmunoprecipitation experiments showed that TCTP forms a complex with ATM and γH2A.X, in agreement with its distinct localization with the foci of the DNA damage-marker proteins γH2A.X, 53BP1, and P-ATM. In cells lacking TCTP, repair of chromosomal damage induced by γ rays was compromised significantly. TCTP also was shown to interact with p53 and the DNA-binding subunits, Ku70 and Ku80, of DNA-dependent protein kinase. TCTP knockdown led to decreased levels of Ku70 and Ku80 in nuclei of irradiated cells and attenuated their DNA-binding activity. It also attenuated the radiation-induced G(1) delay but prolonged the G(2) delay. TCTP therefore may play a critical role in maintaining genomic integrity in response to DNA-damaging agents.
authors.affiliation: Departments of Radiology, Pharmacology and Physiology, and Biochemistry and Molecular Biology, New Jersey Medical School Cancer Center, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Sonia M
authors.initials: SM
authors.lastname: de Toledo
authors.forename: Badri N
authors.initials: BN
authors.lastname: Pandey
authors.forename: Guozheng
authors.initials: G
authors.lastname: Guo
authors.forename: Debkumar
authors.initials: D
authors.lastname: Pain
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Edouard I
authors.initials: EI
authors.lastname: Azzam
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000528:radiation effects; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D016193:G1 Phase / Q000528:radiation effects; D016195:G2 Phase / Q000528:radiation effects; D005720:Gamma Rays; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D000072200:Ku Autoantigen; D051379:Mice; D008809:Mice, Inbred C3H; D011485:Protein Binding / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000528:radiation effects*; D000090324:Tumor Protein, Translationally-Controlled 1; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D034961:Antigens, Nuclear; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; C000715647:TPT1 protein, human; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen