Trp-tRNA synthetase bridges DNA-PKcs to PARP-1 to link IFN-γ and p53 signaling

Mathew Sajish, Quansheng Zhou, Shuji Kishi, Delgado M. Valdez, Mili Kapoor, Min Guo, Sunhee Lee, Sunghoon Kim, Xiang Lei Yang, Paul Schimmel

Research output: Contribution to journalReview article

53 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)547-554
Number of pages8
JournalNature Chemical Biology
Volume8
Issue number6
DOIs
Publication statusPublished - 2012 Jun

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Sajish, M., Zhou, Q., Kishi, S., Valdez, D. M., Kapoor, M., Guo, M., Lee, S., Kim, S., Yang, X. L., & Schimmel, P. (2012). Trp-tRNA synthetase bridges DNA-PKcs to PARP-1 to link IFN-γ and p53 signaling. Nature Chemical Biology, 8(6), 547-554. https://doi.org/10.1038/nchembio.937