Human Tyr-tRNA synthetase is a potent PARP-1 activating effector target for resveratrol

Resveratrol (RSV) is reported to extend life span(1,2) and provide cardio-neuro-protective(3), anti-diabetic(4), and anti-cancer effects(3,5) by initiating a stress response(2) that induces survival genes. Because human tyrosyl tRNA synthetase (TyrRS) translocates to the nucleus under stress conditions(6), we considered the possibility that the tyrosine-like phenolic ring of RSV might fit into the active site pocket to effect a nuclear role. Here we present a 2.1Å co-crystal structure of RSV bound to the active site of TyrRS. RSV nullified the catalytic activity and redirected TyrRS to a nuclear function, stimulating NAD(+)-dependent auto-poly-ADP-ribosylation of PARP-1. Downstream activation of key stress signaling pathways were causally connected to TyrRS-PARP-1-NAD(+) collaboration. This collaboration was also demonstrated in the mouse, and was specifically blocked in vivo by a RSV-displacing tyrosyl adenylate analog. In contrast to functionally diverse tRNA synthetase catalytic nulls created by alternative splicing events that ablate active sites(7), here a non-spliced TyrRS catalytic null reveals a new PARP-1- and NAD(+)-dependent dimension to the physiological mechanism of RSV.