Genome-wide Identification and Quantitative Analysis of Cleaved tRNA Fragments Induced by Cellular Stress

Saikia, Mridusmita; Krokowski, Dawid; Guan, Bo; Ivanov, Pavel; Parisien, Marc; Hu, Guobin; Anderson, Paul; Pan, Tao; Hatzoglou, Maria

doi:10.1074/jbc.m112.371799

Cited by 187 publications

(201 citation statements)

References 65 publications

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“…Third, tRNA species that generate SHOT-RNAs appear to be different from those producing tiRNAs. tiRNAs are widely produced from various tRNAs such as tRNA Ala , tRNA Cys , and tRNA Ser (10,15,16,34), but SHOT-RNAs derived from these tRNAs were not identified in our analyses. Fourth, although 5′-and 3′-SHOT-RNAs were expressed with similar quantities, tiRNAs have been reported to be asymmetrically expressed with a much greater abundance of 5′-tiRNAs compared with their 3′-counterpart (12,14,35).…”

Section: Discussionmentioning

confidence: 61%

“…First, SHOTRNAs are constitutively expressed in specific sex hormonedependent cancer cells, whereas tiRNA expression is triggered by stress stimuli, which is a widely conserved phenomenon in various cells. Second, it's likely that RNH1 is not involved in SHOT-RNA production, but the reduced levels of RNH1 contribute to tiRNA accumulation (10,34). Third, tRNA species that generate SHOT-RNAs appear to be different from those producing tiRNAs.…”

Section: Discussionmentioning

confidence: 99%

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Sex hormone-dependent tRNA halves enhance cell proliferation in breast and prostate cancers

Honda

Loher

Shigematsu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

295

464

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Sex hormones and their receptors play critical roles in the development and progression of the breast and prostate cancers. Here we report that a novel type of transfer RNA (tRNA)-derived small RNA, termed Sex HOrmone-dependent TRNA-derived RNAs (SHOTRNAs), are specifically and abundantly expressed in estrogen receptor (ER)-positive breast cancer and androgen receptor (AR)-positive prostate cancer cell lines. SHOT-RNAs are not abundantly present in ER − breast cancer, AR − prostate cancer, or other examined cancer cell lines from other tissues. ER-dependent accumulation of SHOT-RNAs is not limited to a cell culture system, but it also occurs in luminal-type breast cancer patient tissues. SHOT-RNAs are produced from aminoacylated mature tRNAs by angiogenin-mediated anticodon cleavage, which is promoted by sex hormones and their receptors. Resultant 5′-and 3′-SHOT-RNAs, corresponding to 5′-and 3′-tRNA halves, bear a cyclic phosphate (cP) and an amino acid at the 3′-end, respectively. By devising a "cP-RNA-seq" method that is able to exclusively amplify and sequence cP-containing RNAs, we identified the complete repertoire of 5′-SHOT-RNAs. Furthermore, 5′-SHOT-RNA, but not 3′-SHOT-RNA, has significant functional involvement in cell proliferation. These results have unveiled a novel tRNA-engaged pathway in tumorigenesis of hormone-dependent cancers and implicate SHOT-RNAs as potential candidates for biomarkers and therapeutic targets.tRNA | tRNA half | sex hormone | breast cancer | prostate cancer

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Sex hormone-dependent tRNA halves enhance cell proliferation in breast and prostate cancers

Honda

Loher

Shigematsu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

295

464

View full text Add to dashboard Cite

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“…They were later observed in unstressed human cells (Kawaji et al ., 2008; Fu et al ., 2009). However, their levels in resting cells are very low and often increase significantly only during stress conditions (Saikia et al ., 2012). Our group and others detected tRNA‐derived small RNAs circulating in mouse and human bloodstream (Meiri et al ., 2010; Dhahbi et al ., 2013a,b, 2014; Dhahbi, 2014a).…”

Section: Introductionmentioning

confidence: 99%

Circulating microRNA signature of genotype‐by‐age interactions in the long‐lived Ames dwarf mouse

et al. 2015

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SummaryRecent evidence demonstrates that serum levels of specific miRNAs significantly change with age. The ability of circulating sncRNAs to act as signaling molecules and regulate a broad spectrum of cellular functions implicates them as key players in the aging process. To discover circulating sncRNAs that impact aging in the long‐lived Ames dwarf mice, we conducted deep sequencing of small RNAs extracted from serum of young and old mice. Our analysis showed genotype‐specific changes in the circulating levels of 21 miRNAs during aging [genotype‐by‐age interaction (GbA)]. Genotype‐by‐age miRNAs showed four distinct expression patterns and significant overtargeting of transcripts involved in age‐related processes. Functional enrichment analysis of putative and validated miRNA targets highlighted cellular processes such as tumor suppression, anti‐inflammatory response, and modulation of Wnt, insulin, mTOR, and MAPK signaling pathways, among others. The comparative analysis of circulating GbA miRNAs in Ames mice with circulating miRNAs modulated by calorie restriction (CR) in another long‐lived mouse suggests CR‐like and CR‐independent mechanisms contributing to longevity in the Ames mouse. In conclusion, we showed for the first time a signature of circulating miRNAs modulated by age in the long‐lived Ames mouse.

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“…ANG enters cells via a receptor-mediated process that delivers it to the cytoplasm and the nucleus (5,6). In the cytoplasm, ANG cleaves the anticodon loops of mature tRNAs to produce 5′-and 3′-fragments that are designated as tRNA-derived, stress-induced RNAs (tiRNAs) (4,7). We found that a subset of 5′-tiRNAs, but not 3′-tiRNAs, inhibits translation initiation and triggers the assembly of stress granules (SGs) (8,9), RNA granules implicated in the pathogenesis of ALS (8).…”

mentioning

confidence: 99%

G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments

Ivanov

O’Day

Emara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Angiogenin (ANG) is a stress-activated ribonuclease that promotes the survival of motor neurons. Ribonuclease inactivating point mutations are found in a subset of patients with ALS, a fatal neurodegenerative disease with no cure. We recently showed that ANG cleaves tRNA within anticodon loops to produce 5′-and 3′-fragments known as tRNA-derived, stress-induced RNAs (tiRNAs). Selected 5′-tiRNAs (e.g., tiRNA Ala , tiRNA Cys ) cooperate with the translational repressor Y-box binding protein 1 (YB-1) to displace the cap-binding complex eIF4F from capped mRNA, inhibit translation initiation, and induce the assembly of stress granules (SGs). Here, we show that translationally active tiRNAs assemble unique G-quadruplex (G4) structures that are required for translation inhibition. We show that tiRNA Ala binds the cold shock domain of YB-1 to activate these translational reprogramming events. We discovered that 5′-tiDNA Ala (the DNA equivalent of 5′-tiRNA Ala ) is a stable tiRNA analog that displaces eIF4F from capped mRNA, inhibits translation initiation, and induces the assembly of SGs. The 5′-tiDNA Ala also assembles a G4 structure that allows it to enter motor neurons spontaneously and trigger a neuroprotective response in a YB-1-dependent manner. Remarkably, the ability of 5′-tiRNA Ala to induce SG assembly is inhibited by G4 structures formed by pathological GGGGCC repeats found in C9ORF72, the most common genetic cause of ALS, suggesting that functional interactions between G4 RNAs may contribute to neurodegenerative disease.tRNA | angiogenin | stress | C9ORF72 | amyotrophic lateral sclerosis

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Genome-wide Identification and Quantitative Analysis of Cleaved tRNA Fragments Induced by Cellular Stress

Cited by 187 publications

References 65 publications

Sex hormone-dependent tRNA halves enhance cell proliferation in breast and prostate cancers

Sex hormone-dependent tRNA halves enhance cell proliferation in breast and prostate cancers

Circulating microRNA signature of genotype‐by‐age interactions in the long‐lived Ames dwarf mouse

G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments

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