Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Abstract

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.

Biochemical Characterization of the Lysine Acetylation of Tyrosyl‐tRNA Synthetase in Escherichia coli

“…This acetylation could activate DNA repair genes downstream of transcription factor E2F1 to protect against DNA damage in mammalian cells and zebrafish. [9] …”

Reversible lysine acetylation regulates nuclear translocation of TyrRS to counteract genotoxic oxidative stress

“…Our study provides another evidence that PCAF and SIRT1 acting the reversible acetylation in TyrRS regulate its nuclear transport to involve with DNA damage repair, as proved in our in vivo models. 1 The present study not only reveals an unknown regulatory mechanism linking posttranslational modification to tRNA synthetases TyrRS but also enriches our knowledge of the regulatory pathway between PCAF/SIRT1 and DNA damage response. More importantly, we found that K244 acetylation of TyrRS is protective against DNA damage, suggesting a potential therapeutic opportunity to treat DNA-damage-associated diseases by targeting the K244 residue of TyrRS.…”

“…10 Consistent with this finding, we demonstrated that resveratrol increased the acetylation level of TyrRS at K244 site in a dose-dependent manner through upregulating the expression of PCAF. 1 Together, these data suggest that under oxidative stress, PARP1 activation is due to negative feedback among SIRT1, TyrRS, and PARP1.…”

“…1 Aminoacyl-tRNA synthetases (AARSs) catalyze the first step of protein synthesis by esterifying specific amino acids on the 3 0 ends of their cognate tRNAs. AARSs family contain 20 enzymes and are extremely conserved during evolution.…”

“…K244 was identified as the major acetylation site of TyrRS, and K244 acetylation significantly decreased TyrRS activity while enhancing its nuclear translocation, thereby protecting against DNA damage in vivo. 1 Additional biochemical studies demonstrated that PCAF acts as the acetyltransferase, and SIRT1 is a bona fide deacetylase of TyrRS, whose deacetylation activity prevents TyrRS nuclear localization. 1 From these results, we propose a model in which reversible acetylation in the nuclear localization signal (NLS) of TyrRS regulates its nuclear transport under oxidative stress (see Fig.…”