title: 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.
authors.affiliation: State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai 200438, People's Republic of China.
authors.forename: Xuanye
authors.initials: X
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai 200438, People's Republic of China.
authors.forename: Chaoqun
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai 200438, People's Republic of China.
authors.forename: Siyu
authors.initials: S
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai 200438, People's Republic of China.
authors.forename: Yunlan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai 200438, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai 200438, People's Republic of China.
authors.forename: Shuan
authors.initials: S
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai 200438, People's Republic of China.
authors.forename: Xueyu
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai 200438, People's Republic of China.
authors.forename: Jixi
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai 200438, People's Republic of China.
authors.forename: Ruilin
authors.initials: R
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai 200438, People's Republic of China yuw@fudan.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D018384:Oxidative Stress / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000378:metabolism; D014448:Tyrosine-tRNA Ligase / Q000378:metabolism*; D015027:Zebrafish; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D050687:E2F1 Transcription Factor; D056564:Sirtuin 1; D014448:Tyrosine-tRNA Ligase; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
keywords: DNA damage repair; acetylation; oxidative stress; sirtuins; tRNA synthetases