Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement

Goodarzi, Hani; Liu, Xuhang; Nguyen, Hoang Cong; Zhang, Steven; Fish, Lisa; Tavazoie, Sohail F.

doi:10.1016/j.cell.2015.02.053

Cited by 685 publications

(846 citation statements)

References 35 publications

(44 reference statements)

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“…As many studies have suggested different functions of tRFs, 8 , 9 , 11 , 28 , 36 , 37 we performed northern blotting to check whether the overexpression of tRNA Leu would generate corresponding fragments. We used 30-bp radioactive probes to detect the 3 mature isoacceptors of tRNA Leu as well as their 3′ and 5′ end-derived fragments.…”

Section: Resultsmentioning

confidence: 99%

“…49 These new roles of tRNAs have been observed in prokaryotes as well as eukaryotes, and they are involved in various cellular phenomena, including haeme and chlorophyll biosynthesis, antibiotic cellular permeability, energy metabolism, amino acid biosynthesis and protein degradation, reverse transcription of viruses, cell apoptosis and survival, and cancer progression. 4-6 , 10 , 37 , 50-55 In this study, we investigated the novel functions of tRNAs, especially tRNA Leu , which promoted cell proliferation via RSK/MSK signaling.…”

Section: Discussionmentioning

confidence: 99%

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Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

et al. 2018

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While transfer-RNAs (tRNAs) are known to transport amino acids to ribosome, new functions are being unveiled from tRNAs and their fragments beyond protein synthesis. Here we show that phosphorylation of 90-kDa RPS6K (ribosomal proteins S6 kinase) was enhanced by tRNALeu overexpression under amino acids starvation condition. The phosphorylation of 90-kDa RPS6K was decreased by siRNA specific to tRNALeu and was independent to mTOR (mammalian target of rapamycin) signaling. Among the 90-kDa RPS6K family, RSK1 (ribosomal S6 kinase 1) and MSK2 (mitogen-and stress-activated protein kinase 2) were the major kinases phosphorylated by tRNALeu overexpression. Through SILAC (stable isotope labeling by/with amino acids in cell culture) and combined mass spectrometry analysis, we identified EBP1 (ErbB3-binding protein 1) as the tRNALeu-binding protein. We suspected that the overexpression of free tRNALeu would reinforce ErbB2/ErbB3 signaling pathway by disturbing the interaction between ErbB3 and EBP1, resulting in RSK1/MSK2 phosphorylation, improving cell proliferation and resistance to death. Analysis of samples from patients with breast cancer also indicated an association between tRNALeu overexpression and the ErbB2-positive population. Our results suggested a possible link between tRNALeu overexpression and RSK1/MSK2 activation and ErbB2/ErbB3 signaling.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

et al. 2018

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“…32,[63][64][65] The resulting fragments have been demonstrated to bind and inhibit translation machinery, 66 as well as bind and destabilize mRNAs directly. 67 In mouse epidermal stem cells, the expression level of the RNA m 5 C methyltransferase NSUN2 is low but increases over the course of differentiation. This occurs with a concomitant increase in protein translation that is, counter intuitively, not correlated with increased proliferation.…”

Section: Trnamentioning

confidence: 99%

“…Deletion of NSUN2 results in tRNA hypomethylation, accumulation of tRNA fragments, and reduced translation, favoring the stem cell state. 67 By this mechanism, loss of NSUN2 enhances the self-renewal of stem cells in a tumor setting as well, but it renders them sensitive to stress because they are unable to activate stress response pathways that require tRNA methylation. How tRNA fragments influence cell biology more broadly remains to be worked out.…”

Section: Trnamentioning

confidence: 99%

“…How tRNA fragments influence cell biology more broadly remains to be worked out. However, the fact that their accumulation has already been connected to neuronal loss, 65 cancer progression, 67 and stem cell differentiation 68 suggests that this may represent a general mechanism by which tRNA modifications can influence cell signaling processes in both normal and disease states.…”

Section: Trnamentioning

confidence: 99%

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Publisher's Note

2017

RNA Biology

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RNA modifications have long been known to be central in the proper function of tRNA and rRNA. While chemical modifications in mRNA were discovered decades ago, their function has remained largely mysterious until recently. Using enrichment strategies coupled to next generation sequencing, multiple modifications have now been mapped on a transcriptome-wide scale in a variety of contexts. We now know that RNA modifications influence cell biology by many different mechanisms -by influencing RNA structure, by tuning interactions within the ribosome, and by recruiting specific binding proteins that intersect with other signaling pathways. They are also dynamic, changing in distribution or level in response to stresses such as heat shock and nutrient deprivation. Here, we provide an overview of recent themes that have emerged from the substantial progress that has been made in our understanding of chemical modifications across many major RNA classes in eukaryotes.

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From tRNA to miRNA: RNA‐folding contributes to correct entry into noncoding RNA pathways

Hasler

Meister

2016

FEBS Letters

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Edited by Wilhelm JustAlthough RNA are synthesized as single-stranded molecules, most of them are characterized by extensive secondary structures. Two RNA that require distinct folding for biogenesis and function are miRNA and tRNA. While miRNA are processed from hairpin-containing precursors, tRNA are folded into characteristic L-shaped structures. In addition, tRNA and their precursors are a rich source of RNA fragments. Recent findings suggest that their production might be determined by structural characteristics of the tRNA substrates. Importantly, correct folding of pre-tRNA is assisted by the Lupus autoantigen La, an RNA chaperone. In this context, La interacts with pre-tRNA to prevent alternative foldings leading to mis-channeling into the miRNA pathway. Thus, RNA chaperones also function as gatekeepers for correct RNA pathway selection.Keywords: Lupus autoantigen La; miRNA; RNA chaperone; tRNA fragments RNA molecules are characterized by secondary structures that are important for their individual functions. Such structures can be restricted to short sequence stretches or can involve distant regions of large RNA molecules as known for the complex folding of rRNA, for example [1]. Shorter RNA, such as tRNA, small nuclear RNA (snRNA), or small nucleolar RNA (snoRNA), often adopt specific structures providing RNA-or protein-binding platforms or scaffolds for ribonucleoprotein particle (RNP) formation. Other RNA including miRNA or short interfering RNA (siRNA) use distinct folding strategies of precursor molecules, which allow efficient processing to their mature and functional forms [2]. Therefore, adopting the correct structure is vital for any RNA molecule and processes have evolved that support RNA folding and the stability of RNA structures [3]. Biogenesis of tRNAOne class of RNA that requires a very specific folding to fulfill its functions is tRNA. In addition, tRNA are highly modified at various nucleotides and these alterations can also dramatically affect the secondary structure (reviewed in [4]). In eukaryotes, tRNA are transcribed by RNA polymerase III (pol III) as precursor molecules that contain a 5 0 extension and a 3 0 trailer terminating with a stretch of U residues. The 5 0 extension (often referred to as 5 0 leader) is removed by RNase P. The human RNase P is a RNP complex composed of 10 protein subunits and the noncoding RNA H1 (or RPPH1) [5], which is transcribed by pol III as well. RNA H1 is the catalytic subunit and therefore RNase P was among the first ribozymes that has been discovered [6].The canonical processing of the 3 0 end of pre-tRNA requires the endonucleolytic cleavage activity of a Abbreviations ANG, angiogenin; LARP, La-related protein; RBP, RNA-binding protein; RISC, RNA-induced silencing complex; RNP, ribonucleoprotein particle; siRNA, short interfering RNA; snoRNA, small nucleolar RNA; snRNA, small nuclear RNA; tRF, tRNA fragment; TSEN, tRNA-splicing endonuclease.

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Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement

Cited by 685 publications

References 35 publications

Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

Publisher's Note

From tRNA to miRNA: RNA‐folding contributes to correct entry into noncoding RNA pathways

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