Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):687-692. doi: 10.1073/pnas.1608488114. Epub 2017 Jan 9.


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.

Keywords: DNA damage repair; acetylation; oxidative stress; sirtuins; tRNA synthetases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus / metabolism*
  • DNA Damage / physiology*
  • E2F1 Transcription Factor / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Oxidative Stress / physiology*
  • Protein Transport / physiology
  • Signal Transduction / physiology
  • Sirtuin 1 / metabolism
  • Tyrosine-tRNA Ligase / metabolism*
  • Zebrafish
  • p300-CBP Transcription Factors / metabolism


  • E2F1 Transcription Factor
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Sirtuin 1
  • Tyrosine-tRNA Ligase