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

A human tRNA synthetase connects resveratrol to stress signalling. Many reports highlight the health benefits of resveratrol, a natural ingredient of grape skins and red wine. It is thought to extend lifespan and protect against a variety of diseases by initiating a stress response that induces survival genes. Here Mathew Sajish and Paul Schimmel present a 2.1 Å co-crystal structure of resveratrol bound to the active site of human tyrosyl tRNA synthetase (TyrRS), an enzyme that translocates to the nucleus under stress conditions. They see that resveratrol inhibits catalytic activity and redirects TyrRS to a nuclear function, stimulating NAD+-dependent auto-poly-ADP-ribosylation of PARP-1 (poly(ADP-ribose) polymerase 1) and leading to the activation of key stress signalling pathways. This work suggests an alternative mechanism of action for resveratrol, additional to its binding and activation of the histone deacetylase SIRT1. Resveratrol is reported to extend lifespan1,2 and provide cardio-neuro-protective3, anti-diabetic4, and anti-cancer effects3,5 by initiating a stress response2 that induces survival genes. Because human tyrosyl transfer-RNA (tRNA) synthetase (TyrRS) translocates to the nucleus under stress conditions6, 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 sites7, here a non-spliced TyrRS catalytic null reveals a new PARP1- and NAD+-dependent dimension to the physiological mechanism of resveratrol.