title: Genome-wide identification and quantitative analysis of cleaved tRNA fragments induced by cellular stress.
abstract: Certain stress conditions can induce cleavage of tRNAs around the anticodon loop via the use of the ribonuclease angiogenin. The cellular factors that regulate tRNA cleavage are not well known. In this study we used normal and eIF2α phosphorylation-deficient mouse embryonic fibroblasts and applied a microarray-based methodology to identify and compare tRNA cleavage patterns in response to hypertonic stress, oxidative stress (arsenite), and treatment with recombinant angiogenin. In all three scenarios mouse embryonic fibroblasts deficient in eIF2α phosphorylation showed a higher accumulation of tRNA fragments including those derived from initiator-tRNA(Met). We have shown that tRNA cleavage is regulated by the availability of angiogenin, its substrate (tRNA), the levels of the angiogenin inhibitor RNH1, and the rates of protein synthesis. These conclusions are supported by the following findings: (i) exogenous treatment with angiogenin or knockdown of RNH1 increased tRNA cleavage; (ii) tRNA fragment accumulation was higher during oxidative stress than hypertonic stress, in agreement with a dramatic decrease of RNH1 levels during oxidative stress; and (iii) a positive correlation was observed between angiogenin-mediated tRNA cleavage and global protein synthesis rates. Identification of the stress-specific tRNA cleavage mechanisms and patterns will provide insights into the role of tRNA fragments in signaling pathways and stress-related disorders.
authors.affiliation: Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA. mxs945@case.edu
authors.forename: Mridusmita
authors.initials: M
authors.lastname: Saikia
authors.forename: Dawid
authors.initials: D
authors.lastname: Krokowski
authors.forename: Bo-Jhih
authors.initials: BJ
authors.lastname: Guan
authors.forename: Pavel
authors.initials: P
authors.lastname: Ivanov
authors.forename: Marc
authors.initials: M
authors.lastname: Parisien
authors.forename: Guo-fu
authors.initials: GF
authors.lastname: Hu
authors.forename: Paul
authors.initials: P
authors.lastname: Anderson
authors.forename: Tao
authors.initials: T
authors.lastname: Pan
authors.forename: Maria
authors.initials: M
authors.lastname: Hatzoglou
mesh_terms: D000818:Animals; D000926:Anticodon / Q000737:chemistry / Q000235:genetics; D018053:Arsenites / Q000633:toxicity; D001483:Base Sequence; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D016678:Genome / Q000235:genetics*; D006982:Hypertonic Solutions / Q000494:pharmacology; D051379:Mice; D009690:Nucleic Acid Conformation; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism*; D012259:Ribonuclease, Pancreatic / Q000037:antagonists & inhibitors / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D000926:Anticodon; D018053:Arsenites; D015852:Eukaryotic Initiation Factor-2; D006982:Hypertonic Solutions; D012333:RNA, Messenger; D012343:RNA, Transfer; C046366:angiogenin; D012259:Ribonuclease, Pancreatic; C015001:arsenite