Resvertrol targets a human tRNA synthetase for activation of NAD+-dependent PARP1

 

Resveratrol (RSV) is well known for its effect of lifespan extension and against serious diseases such as diabetic and cancer. Previous studies showed it enable to induce survival genes by starting a stress response. Mathew Sajish and Paul Schimmel found RSV interacts with tyrosyl transfer-RNA (tRNA) synthetase (TyrRS), which translocates to the nucleus in response to stress, to initiating its effect in nuclear. The letter was published online in Nature.

 

Researchers found RSV strongly inhibits TyrRS by binding to its active site with a co-crystal structure. The interaction nullifies the catalytic activity of TyrRS, consequently mediates TyrRS to stimulate NAD⁺-dependent auto-poly-ADP-ribosylation of poly polymerase 1 (PARP1), a main regulator of NAD⁺ metabolism and associated signaling. The TyrRS-PARP1-NAD+ collaboration can be blocked by RSV after replacing tyrosyl adenylate analogue by RSV in vivo. Moreover, a short interfering RNA (siRNA), that interfered PARP1 activities, significantly reduce the expression level of RSV-targeted genes encoding Hsp72, p-AMPK, SIR1, FOXO3A, etc. The findings indicate a critical role of TyrRS in PARP1 induced-stress response activated by RSV.

 

Reference:
Nature. 2014 Dec 22.10.1038/nature14028. 

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S2178	AG-14361	AG14361 is a potent inhibitor of PARP1 with Ki of <5 nM in a cell-free assay. It is at least 1000-fold more potent than the benzamides.

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