ZFIN ID: ZDB-PUB-120730-4
Trp-tRNA synthetase bridges DNA-PKcs to PARP-1 to link IFN-γ and p53 signaling
Sajish, M., Zhou, Q., Kishi, S., Valdez, D.M., Kapoor, M., Guo, M., Lee, S., Kim, S., Yang, X.L., and Schimmel, P.
Date: 2012
Source: Nature Chemical Biology   8(6): 547-554 (Journal)
Registered Authors: Kishi, Shuji
Keywords: none
MeSH Terms:
  • Animals
  • Catalytic Domain
  • Cell Culture Techniques
  • Cell Nucleus/drug effects
  • Cell Nucleus/enzymology
  • Cell Nucleus/metabolism
  • Cytoplasm/drug effects
  • Cytoplasm/enzymology
  • Cytoplasm/metabolism
  • DNA-Activated Protein Kinase/genetics
  • DNA-Activated Protein Kinase/metabolism*
  • Electrophoresis, Polyacrylamide Gel
  • Embryo, Nonmammalian/enzymology
  • HeLa Cells
  • Humans
  • Immunoprecipitation
  • Interferon-gamma/pharmacology*
  • Interferon-gamma/physiology
  • Microscopy, Confocal
  • Models, Molecular
  • Phosphorylation
  • Poly(ADP-ribose) Polymerases/genetics
  • Poly(ADP-ribose) Polymerases/metabolism*
  • Protein Interaction Maps
  • Signal Transduction/drug effects*
  • Transfection
  • Tryptophan-tRNA Ligase/genetics
  • Tryptophan-tRNA Ligase/metabolism*
  • Tumor Suppressor Protein p53/genetics
  • Tumor Suppressor Protein p53/metabolism*
  • Zebrafish/embryology
  • Zebrafish/metabolism
PubMed: 22504299 Full text @ Nat. Chem. Biol.
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.

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