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J. Cell Biol. 185 (1): 35-42

Copyright © 2009 by the Rockefeller University Press.

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Angiogenin cleaves tRNA and promotes stress-induced translational repression

Satoshi Yamasaki1, Pavel Ivanov1, Guo-fu Hu2, , and Paul Anderson1

1 Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, and 2 Department of Pathology, Harvard Medical School, Boston, MA 02115

Correspondence to Paul Anderson: panderson{at}rics.bwh.harvard.edu

Abstract: Stress-induced phosphorylation of eIF2{alpha} inhibits global protein synthesis to conserve energy for repair of stress-induced damage. Stress-induced translational arrest is observed in cells expressing a nonphosphorylatable eIF2{alpha} mutant (S51A), which indicates the existence of an alternative pathway of translational control. In this paper, we show that arsenite, heat shock, or ultraviolet irradiation promotes transfer RNA (tRNA) cleavage and accumulation of tRNA-derived, stress-induced small RNAs (tiRNAs). We show that angiogenin, a secreted ribonuclease, is required for stress-induced production of tiRNAs. Knockdown of angiogenin, but not related ribonucleases, inhibits arsenite-induced tiRNA production and translational arrest. In contrast, knockdown of the angiogenin inhibitor RNH1 enhances tiRNA production and promotes arsenite-induced translational arrest. Moreover, recombinant angiogenin, but not RNase 4 or RNase A, induces tiRNA production and inhibits protein synthesis in the absence of exogenous stress. Finally, transfection of angiogenin-induced tiRNAs promotes phospho-eIF2{alpha}–independent translational arrest. Our results introduce angiogenin and tiRNAs as components of a phospho-eIF2{alpha}–independent stress response program.

S. Yamasaki and P. Ivanov contributed equally to this paper.

Abbreviations used in this paper: MEF, mouse embryo fibroblast; piRNA, PIWI-associated RNA; tiRNA, transfer RNA-derived stress-induced RNA.

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