Tyrosine Inhibits TyrRS-mediated DNA Repair and Induces Neuronal Oxidative DNA Damage

Abstract Human aging and neurodegenerative diseases accumulate oxidative DNA damage-associated mutations in neurons. Circadian-regulated tyrosine (Tyr) is increased during aging and in Alzheimer’s Disease (AD). Tyr exacerbates the cognitive decline in the elderly and AD patients. Tyrosyl-tRNA synthetase (TyrRS) that activates Tyr for protein synthesis and participates in DNA repair is depleted in the affected brain regions of AD patients through an unknown mechanism. Here, we found that increased Tyr levels decrease the nuclear and neurite levels of TyrRS in neurons and cause oxidative DNA damage. Although Tyr inhibits protein synthesis at the elongation step, dopamine (DA)- a neurotransmitter derived from Tyr increases TyrRS levels. We previously showed that Tyr inhibits TyrRS-mediated activation of poly-ADP-ribose polymerase 1 (PARP1), a modulator of DNA repair. We now found that trans-resveratrol (trans-RSV) that binds to TyrRS mimicking ‘Tyr conformation’ decreases TyrRS, inhibits DNA repair and induces neurotoxicity. Conversely, cis-RSV binds to TyrRS mimicking a ‘Tyr-free conformation,’ increases TyrRS, facilitates DNA repair, and protects neurons against multiple neurotoxic agents in a TyrRS-dependent manner. Our results suggest that increased Tyr levels may have causal effects in human aging and neurocognitive disorders and offer a plausible explanation to divergent results obtained in clinical trials using RSV.