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A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol

Academic Article
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Overview

authors

  • Sajish, M.
  • Schimmel, Paul

publication date

  • March 2015

journal

  • Nature  Journal

abstract

  • Resveratrol is reported to extend lifespan and provide cardio-neuro-protective, anti-diabetic, and anti-cancer effects by initiating a stress response that induces survival genes. Because human tyrosyl transfer-RNA (tRNA) synthetase (TyrRS) translocates to the nucleus under stress conditions, we considered the possibility that the tyrosine-like phenolic ring of resveratrol might fit into the active site pocket to effect a nuclear role. Here we present a 2.1 Å co-crystal structure of resveratrol bound to the active site of TyrRS. Resveratrol nullifies the catalytic activity and redirects TyrRS to a nuclear function, stimulating NAD(+)-dependent auto-poly-ADP-ribosylation of poly(ADP-ribose) polymerase 1 (PARP1). Downstream activation of key stress signalling pathways are causally connected to TyrRS-PARP1-NAD(+) collaboration. This collaboration is also demonstrated in the mouse, and is specifically blocked in vivo by a resveratrol-displacing tyrosyl adenylate analogue. In contrast to functionally diverse tRNA synthetase catalytic nulls created by alternative splicing events that ablate active sites, here a non-spliced TyrRS catalytic null reveals a new PARP1- and NAD(+)-dependent dimension to the physiological mechanism of resveratrol.

subject areas

  • Alternative Splicing
  • Animals
  • Biocatalysis
  • Catalytic Domain
  • Cell Nucleus
  • Crystallography, X-Ray
  • Culture Media, Serum-Free
  • Enzyme Activation
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Poly Adenosine Diphosphate Ribose
  • Poly(ADP-ribose) Polymerases
  • Protein Conformation
  • Signal Transduction
  • Sirtuin 1
  • Sirtuins
  • Stilbenes
  • Tyrosine-tRNA Ligase
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Identity

PubMed Central ID

  • PMC4368482

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature14028

PubMed ID

  • 25533949
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Additional Document Info

start page

  • 370

end page

  • 373

volume

  • 519

issue

  • 7543

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