title: Trp-tRNA synthetase bridges DNA-PKcs to PARP-1 to link IFN-γ and p53 signaling.
abstract: Interferon-γ (IFN-γ) engenders strong antiproliferative responses, in part through activation of p53. However, the long-known IFN-γ-dependent upregulation of human Trp-tRNA synthetase (TrpRS), a cytoplasmic enzyme that activates tryptophan to form Trp-AMP in the first step of protein synthesis, is unexplained. Here we report a nuclear complex of TrpRS with the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and with poly(ADP-ribose) polymerase 1 (PARP-1), the major PARP in human cells. The IFN-γ-dependent poly(ADP-ribosyl)ation of DNA-PKcs (which activates its kinase function) and concomitant activation of the tumor suppressor p53 were specifically prevented by Trp-SA, an analog of Trp-AMP that disrupted the TrpRS-DNA-PKcs-PARP-1 complex. The connection of TrpRS to p53 signaling in vivo was confirmed in a vertebrate system. These and further results suggest an unexpected evolutionary expansion of the protein synthesis apparatus to a nuclear role that links major signaling pathways.
authors.affiliation: The Skaggs Institute for Chemical Biology, Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Mathew
authors.initials: M
authors.lastname: Sajish
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Zhou
authors.forename: Shuji
authors.initials: S
authors.lastname: Kishi
authors.forename: Delgado M
authors.initials: DM
authors.lastname: Valdez
authors.forename: Mili
authors.initials: M
authors.lastname: Kapoor
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.forename: Sunhee
authors.initials: S
authors.lastname: Lee
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
authors.forename: Paul
authors.initials: P
authors.lastname: Schimmel
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D018929:Cell Culture Techniques; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004625:Embryo, Nonmammalian / Q000201:enzymology; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000494:pharmacology* / Q000502:physiology; D018613:Microscopy, Confocal; D008958:Models, Molecular; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D060066:Protein Interaction Maps; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D014369:Tryptophan-tRNA Ligase / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051747:DNA-Activated Protein Kinase; D014369:Tryptophan-tRNA Ligase