Trp-tRNA synthetase bridges DNA-PKcs to PARP-1 to link IFN-γ and p53 signaling
- Authors
- Sajish, M., Zhou, Q., Kishi, S., Valdez, D.M., Kapoor, M., Guo, M., Lee, S., Kim, S., Yang, X.L., and Schimmel, P.
- ID
- ZDB-PUB-120730-4
- 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.
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.