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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / genetics
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Animals
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BRCA1 Protein / biosynthesis
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Cell Line, Tumor
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Cell Nucleus / genetics
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Cell Nucleus / metabolism*
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DNA Breaks, Double-Stranded
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DNA Damage / genetics*
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DNA Repair / genetics*
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E2F1 Transcription Factor / metabolism
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Enzyme Activation
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HEK293 Cells
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HeLa Cells
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Histone Deacetylase 1 / antagonists & inhibitors
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Histone Deacetylase 1 / metabolism
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Histone Deacetylase Inhibitors / pharmacology
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Humans
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Hydroxamic Acids / pharmacology
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Morpholinos / genetics
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Oxidative Stress / genetics*
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Protein Structure, Tertiary
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Rad51 Recombinase / biosynthesis
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Repressor Proteins / metabolism
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Ribonuclease, Pancreatic / metabolism
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Tripartite Motif-Containing Protein 28
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Tyrosine-tRNA Ligase / biosynthesis
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Tyrosine-tRNA Ligase / genetics
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Tyrosine-tRNA Ligase / metabolism*
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Up-Regulation
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Zebrafish
Substances
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BRCA1 Protein
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BRCA1 protein, human
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E2F1 Transcription Factor
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E2F1 protein, human
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Morpholinos
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Repressor Proteins
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trichostatin A
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TRIM28 protein, human
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Tripartite Motif-Containing Protein 28
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RAD51 protein, human
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Rad51 Recombinase
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angiogenin
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Ribonuclease, Pancreatic
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HDAC1 protein, human
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Histone Deacetylase 1
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Tyrosine-tRNA Ligase