Resveratrol targets TyrRS acetylation to protect against radiation‐induced damage

Gao, Panpan; Li, Na; Ji, Kaihua; Wang, Yan; Xu, Chang; Liu, Yang; Wang, Qin; Wang, Jihan; He, Ningning; Sun, Zhao; Du, Liqing; Liu, Qiang

doi:10.1096/fj.201802474rr

Cited by 16 publications

(9 citation statements)

References 43 publications

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“…Moreover, our discovery of TyrRS being a biologically significant and physiologically relevant target of RSV that facilitates the conversion of trans-RSV to cis-RSV suggests that the cis-isomer of RSV is also a major isomer that evokes protective stress response. Other recent studies have also confirmed the TyrRS-PARP1 signaling in mediating the protective effects of RSV [120,229,296,[432][433][434]. However, there are still critical gaps in our knowledge.…”

Section: Cisand Trans-rsv Have Opposite Effects On Tyrrs-regulated Pamentioning

confidence: 93%

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation

2020

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Unlike widely perceived, resveratrol (RSV) decreased the average lifespan and extended only the replicative lifespan in yeast. Similarly, although not widely discussed, RSV is also known to evoke neurite degeneration, kidney toxicity, atherosclerosis, premature senescence, and genotoxicity through yet unknown mechanisms. Nevertheless, in vivo animal models of diseases and human clinical trials demonstrate inconsistent protective and beneficial effects. Therefore, the mechanism of action of RSV that elicits beneficial effects remains an enigma. In a previously published work, we demonstrated structural similarities between RSV and tyrosine amino acid. RSV acts as a tyrosine antagonist and competes with it to bind to human tyrosyl-tRNA synthetase (TyrRS). Interestingly, although both isomers of RSV bind to TyrRS, only the cis-isomer evokes a unique structural change at the active site to promote its interaction with poly-ADPribose polymerase 1 (PARP1), a major determinant of cellular NAD +-dependent stress response. However, retention of trans-RSV in the active site of TyrRS mimics its tyrosine-bound conformation that inhibits the autopoly-ADP-ribos(PAR)ylation of PARP1. Therefore, we proposed that cis-RSV-induced TyrRS-regulated auto-PARylation of PARP1 would contribute, at least in part, to the reported health benefits of RSV through the induction of protective stress response. This observation suggested that trans-RSV would inhibit TyrRS/PARP1mediated protective stress response and would instead elicit an opposite effect compared to cis-RSV. Interestingly, most recent studies also confirmed the conversion of trans-RSV and its metabolites to cis-RSV in the physiological context. Therefore, the finding that cis-RSV and trans-RSV induce two distinct conformations of TyrRS with opposite effects on the auto-PARylation of PARP1 provides a potential molecular basis for the observed dichotomic effects of RSV under different experimental paradigms. However, the fact that natural RSV exists as a diastereomeric mixture of its cis and trans isomers and cis-RSV is also a physiologically relevant isoform has not yet gained much scientific attention. Keywords Resveratrol (RSV). Aminoacyl-tRNA synthetases (aaRSs). Tyrosyl-tRNA synthetase (YARS. TyrRS). Nicotinamide adenine nucleotide (NAD +). Poly-ADP-ribose polymerase (PARP). Sirtuins (SIRT). AMP-activated protein kinase (AMPK). Nicotinamide (NAM) GeroScience

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Section: Cisand Trans-rsv Have Opposite Effects On Tyrrs-regulated Pamentioning

confidence: 93%

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation

2020

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“…In mice, administration of RES attenuates radiation-induced intestinal damage via activation of sirtuin-1 [ 135 ], supporting lymphocyte [ 136 ] and intestinal functions recovery [ 137 ]. Under oxidative stress, RES promotes tyrosyl-tRNA synthetase acetylation, regulates relevant signaling proteins, and reduces apoptosis and DNA damage [ 138 ]. Clinical studies on RES as a normal tissue protector and potential tumor sensitizer are limited [ 139 ], mainly because RES possesses unfavorable bioavailability and pharmacokinetic properties.…”

Section: Medical Countermeasuresmentioning

confidence: 99%

Nuclear and Radiological Emergencies: Biological Effects, Countermeasures and Biodosimetry

et al. 2022

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Atomic and radiological crises can be caused by accidents, military activities, terrorist assaults involving atomic installations, the explosion of nuclear devices, or the utilization of concealed radiation exposure devices. Direct damage is caused when radiation interacts directly with cellular components. Indirect effects are mainly caused by the generation of reactive oxygen species due to radiolysis of water molecules. Acute and persistent oxidative stress associates to radiation-induced biological damages. Biological impacts of atomic radiation exposure can be deterministic (in a period range a posteriori of the event and because of destructive tissue/organ harm) or stochastic (irregular, for example cell mutation related pathologies and heritable infections). Potential countermeasures according to a specific scenario require considering basic issues, e.g., the type of radiation, people directly affected and first responders, range of doses received and whether the exposure or contamination has affected the total body or is partial. This review focuses on available medical countermeasures (radioprotectors, radiomitigators, radionuclide scavengers), biodosimetry (biological and biophysical techniques that can be quantitatively correlated with the magnitude of the radiation dose received), and strategies to implement the response to an accidental radiation exposure. In the case of large-scale atomic or radiological events, the most ideal choice for triage, dose assessment and victim classification, is the utilization of global biodosimetry networks, in combination with the automation of strategies based on modular platforms.

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“…RSV also targets tyrosyl-tRNAsynthetase (TyrRS), involved in protein synthesis, and TyrRS is linked to the regulation of genes associated with HRR (Cao et al, 2017). RSV causes inactivation of TyrRS, its translocation to the nucleus and, therefore, inhibits HRR (Gao et al, 2019).…”

Section: Hdac/kdac Inhibitorsmentioning

confidence: 99%

Emerging Therapeutic Targets Against Toxoplasma gondii: Update on DNA Repair Response Inhibitors and Genotoxic Drugs

Angel

Vanagas

Ruiz

et al. 2020

Front. Cell. Infect. Microbiol.

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Toxoplasma gondii is the causative agent of toxoplasmosis in animals and humans. This infection is transmitted to humans through oocysts released in the feces of the felines into the environment or by ingestion of undercooked meat. This implies that toxoplasmosis is a zoonotic disease and T. gondii is a foodborne pathogen. In addition, chronic toxoplasmosis in goats and sheep is the cause of recurrent abortions with economic losses in the sector. It is also a health problem in pets such as cats and dogs. Although there are therapies against this infection in its acute stage, they are not able to permanently eliminate the parasite and sometimes they are not well tolerated. To develop better, safer drugs, we need to elucidate key aspects of the biology of T. gondii. In this review, we will discuss the importance of the homologous recombination repair (HRR) pathway in the parasite's lytic cycle and how components of these processes can be potential molecular targets for new drug development programs. In that sense, the effect of different DNA damage agents or HHR inhibitors on the growth and replication of T. gondii will be described. Multitarget drugs that were either associated with other targets or were part of general screenings are included in the list, providing a thorough revision of the drugs that can be tested in other scenarios.

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Resveratrol targets TyrRS acetylation to protect against radiation‐induced damage

Cited by 16 publications

References 43 publications

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation

Nuclear and Radiological Emergencies: Biological Effects, Countermeasures and Biodosimetry

Emerging Therapeutic Targets Against Toxoplasma gondii: Update on DNA Repair Response Inhibitors and Genotoxic Drugs

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