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

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71 Citations (Scopus)


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
Issue number6
Publication statusPublished - 2012 Jun

Bibliographical note

Funding Information:
We thank D. Chen (University of Texas Southwestern Medical School) for the DNA-PKcs clone and P. Chang (Massachusetts Institute of Technology) for the ZZ-PARP-1 clone. This work was supported by grants GM15539 and GM23562 (to P.S.) and GM088278 (to X.-L.Y.) from the US National Institutes of Health and by a fellowship from the National Foundation for Cancer Research.

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


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