title: Oxidative stress diverts tRNA synthetase to nucleus for protection against DNA damage.
abstract: Tyrosyl-tRNA synthetase (TyrRS) is known for its essential aminoacylation function in protein synthesis. Here we report a function for TyrRS in DNA damage protection. We found that oxidative stress, which often downregulates protein synthesis, induces TyrRS to rapidly translocate from the cytosol to the nucleus. We also found that angiogenin mediates or potentiates this stress-induced translocalization. The nuclear-localized TyrRS activates transcription factor E2F1 to upregulate the expression of DNA damage repair genes such as BRCA1 and RAD51. The activation is achieved through direct interaction of TyrRS with TRIM28 to sequester this vertebrate-specific epigenetic repressor and its associated HDAC1 from deacetylating and suppressing E2F1. Remarkably, overexpression of TyrRS strongly protects against UV-induced DNA double-strand breaks in zebrafish, whereas restricting TyrRS nuclear entry completely abolishes the protection. Therefore, oxidative stress triggers an essential cytoplasmic enzyme used for protein synthesis to translocate to the nucleus to protect against DNA damage.
authors.affiliation: Departments of Chemical Physiology and Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Wei
authors.affiliation: Departments of Chemical Physiology and Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Lan N
authors.initials: LN
authors.lastname: Truong
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Fisch
authors.affiliation: Departments of Chemical Physiology and Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.affiliation: Departments of Chemical Physiology and Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Gardiner
authors.affiliation: Departments of Chemical Physiology and Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Guangsen
authors.initials: G
authors.lastname: Fu
authors.affiliation: Departments of Chemical Physiology and Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Yun-Shiuan Olivia
authors.initials: YO
authors.lastname: Hsu
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Shuji
authors.initials: S
authors.lastname: Kishi
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Su
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wu
authors.affiliation: Departments of Chemical Physiology and Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: xlyang@scripps.edu.
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D019313:BRCA1 Protein / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D004789:Enzyme Activation; D057809:HEK293 Cells; D006367:HeLa Cells; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D060172:Morpholinos / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics*; D017434:Protein Structure, Tertiary; D051135:Rad51 Recombinase / Q000096:biosynthesis; D012097:Repressor Proteins / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D000076183:Tripartite Motif-Containing Protein 28; D014448:Tyrosine-tRNA Ligase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D015027:Zebrafish
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D060172:Morpholinos; D012097:Repressor Proteins; C012589:trichostatin A; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C046366:angiogenin; D012259:Ribonuclease, Pancreatic; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D014448:Tyrosine-tRNA Ligase