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A stress‐induced tyrosine‐tRNA depletion response mediates codon‐based translational repression and growth suppression
Author(s) -
Huh Doowon,
Passarelli Maria C,
Gao Jenny,
Dusmatova Shahnoza N,
Goin Clara,
Fish Lisa,
Pinzaru Alexandra M,
Molina Henrik,
Ren Zhiji,
McMillan Elizabeth A,
Asgharian Hosseinali,
Goodarzi Hani,
Tavazoie Sohail F
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020106696
Subject(s) - biology , psychological repression , transfer rna , tyrosine , translational regulation , genetics , translation (biology) , microbiology and biotechnology , rna , biochemistry , gene , messenger rna , gene expression
Eukaryotic transfer RNAs can become selectively fragmented upon various stresses, generating tRNA‐derived small RNA fragments. Such fragmentation has been reported to impact a small fraction of the tRNA pool and thus presumed to not directly impact translation. We report that oxidative stress can rapidly generate tyrosine‐tRNA GUA fragments in human cells—causing significant depletion of the precursor tRNA. Tyrosine‐tRNA GUA depletion impaired translation of growth and metabolic genes enriched in cognate tyrosine codons. Depletion of tyrosine tRNA GUA or its translationally regulated targets USP3 and SCD repressed proliferation—revealing a dedicated tRNA‐regulated growth‐suppressive pathway for oxidative stress response. Tyrosine fragments are generated in a DIS3L2 exoribonuclease‐dependent manner and inhibit hnRNPA1‐mediated transcript destabilization. Moreover, tyrosine fragmentation is conserved in C. elegans . Thus, tRNA fragmentation can coordinately generate trans ‐acting small RNAs and functionally deplete a tRNA. Our findings reveal the existence of an underlying adaptive codon‐based regulatory response inherent to the genetic code.