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

doi:10.1038/nchembio.937

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

Department of Pharmacy

Research output: Contribution to journal › Review article › peer-review

71 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 language	English
Pages (from-to)	547-554
Number of pages	8
Journal	Nature Chemical Biology
Volume	8
Issue number	6
DOIs	https://doi.org/10.1038/nchembio.937
Publication status	Published - 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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10.1038/nchembio.937

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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.",

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

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.",

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AU - Valdez, Delgado M.

AU - Kapoor, Mili

AU - Guo, Min

AU - Lee, Sunhee

AU - Kim, Sunghoon

AU - Yang, Xiang Lei

AU - Schimmel, Paul

N1 - 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.

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N2 - 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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Trp-tRNA synthetase bridges DNA-PKcs to PARP-1 to link IFN-γ and p53 signaling

Abstract

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