Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage
Significance Aminoacyl-tRNA synthetases (AARSs) comprise a family of 20 enzymes that catalyze the first step of protein synthesis by esterifying specific amino acids to the 3′ ends of their cognate tRNAs. Protein acetylation, an evolutionarily conserved posttranslational modification, has recently been extensively investigated to regulate diverse cellular processes. This work provides the molecular evidence that one of the aminoacyl-tRNA synthetases is modulated by reversible acetylation. This study not only reveals a regulatory mechanism for the tRNA synthetase tyrosyl-tRNA synthetase (TyrRS) due to a posttranslational modification but also enriches knowledge of the regulatory pathway between p300/CBP-associated factor (PCAF)/sirtuin 1 (SIRT1) and the DNA damage/repair response. Tyrosyl-tRNA synthetase (TyrRS) is well known for its essential aminoacylation function in protein synthesis. Recently, TyrRS has been shown to translocate to the nucleus and protect against DNA damage due to oxidative stress. However, the mechanism of TyrRS nuclear localization has not yet been determined. Herein, we report that TyrRS becomes highly acetylated in response to oxidative stress, which promotes nuclear translocation. Moreover, p300/CBP-associated factor (PCAF), an acetyltransferase, and sirtuin 1 (SIRT1), a NAD + -dependent deacetylase, regulate the nuclear localization of TyrRS in an acetylation-dependent manner. Oxidative stress increases the level of PCAF and decreases the level of SIRT1 and deacetylase activity, all of which promote the nuclear translocation of hyperacetylated TyrRS. Furthermore, TyrRS is primarily acetylated on the K244 residue near the nuclear localization signal (NLS), and acetylation inhibits the aminoacylation activity of TyrRS. Molecular dynamics simulations have shown that the in silico acetylation of K244 induces conformational changes in TyrRS near the NLS, which may promote the nuclear translocation of acetylated TyrRS. Herein, we show that the acetylated K244 residue of TyrRS protects against DNA damage in mammalian cells and zebrafish by activating DNA repair genes downstream of transcription factor E2F1. Our study reveals a previously unknown mechanism by which acetylation regulates an aminoacyl-tRNA synthetase, thus affecting the repair pathways for damaged DNA.
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