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Mol Cell. 2014 Oct 23;56(2):323-332. doi: 10.1016/j.molcel.2014.09.006. Epub 2014 Oct 2.

Oxidative stress diverts tRNA synthetase to nucleus for protection against DNA damage.

Author information

1
Departments of Chemical Physiology and Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
3
Department of Metabolism and Aging, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
4
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.

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.

PMID:
25284223
PMCID:
PMC4224670
DOI:
10.1016/j.molcel.2014.09.006
[Indexed for MEDLINE]
Free PMC Article

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