Roles of tRNA-derived fragments in human cancers

Sun, Chunxiao; Fu, Ziyi; Wang, Siwei; Li, Jun; Li, Yongfei; Zhang, Yanhong; Yang, Fan; Chu, Jie; Wu, Hao; Huang, Xiang; Li, Wei; Yin, Yuan

doi:10.1016/j.canlet.2017.10.031

Cited by 116 publications

(109 citation statements)

References 97 publications

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“…Different types of tRNA-derived fragments have been found to have a variety of different functions [29]. 5'-tRHs, but not 3'-tRHs, play a role in inhibiting protein synthesis and promoting the assembly of stress granules [52,53].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, accumulated evidence has demonstrated that these tRNA-derived fragments play important roles in human cancers [23][24][25][26][27][28][29]. Lee YS et al showed that knockdown of tRF-1001 significantly inhibit cell proliferation with specific accumulation of cells in the G2 phase and inhibition of DNA synthesis in prostate cancer [20].…”

Section: Introductionmentioning

confidence: 99%

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tRNA-Derived Fragments as Novel Predictive Biomarkers for Trastuzumab-Resistant Breast Cancer

Sun

Yang

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Resistance to trastuzumab remains a common challenge to HER-2 positive breast cancer. Up until now, the underlying mechanism of trastuzumab resistance is still unclear. tRNA-derived small non-coding RNAs, a new class of small non-coding RNA (sncRNAs), have been observed to play an important role in cancer progression. However, the relationship between tRNA-derived fragments and trastuzumab resistance is still unknown. Methods: We detected the levels of tRNA-derived fragments expression in normal breast epithelial cell lines, trastuzumab-sensitive and -resistant breast cancer cell lines using high-throughput sequencing. qRT-PCR was conducted to validate the differentially expressed fragments in serums from trastuzumab-sensitive and -resistant patients. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the power of specific tRNA-derived fragments. Progression-free survival (PFS) was analyzed using Cox-regression. Results: Our sequence results showed that tRNA-derived fragments were differentially expressed in the HBL-100, SKBR3, and JIMT-1 cell lines. tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN were found significantly upregulated in trastuzumab-resistant patients compared to sensitive individuals, and the ROC analysis showed that tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN were correlated with trastuzumab resistance. In a multivariate analysis, higher levels of tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN expression were associated with significantly shorter PFS in patients with metastatic HER-2 positive breast cancer. Conclusion: Our results suggest that tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN play important roles in trastuzumab resistance. Patients with high levels of tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN expression benefitted less from trastuzumab-based therapy than those that express lower-levels of these molecules. tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN may be potential biomarkers and intervention targets in the clinical treatment of trastuzumab-resistant breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

tRNA-Derived Fragments as Novel Predictive Biomarkers for Trastuzumab-Resistant Breast Cancer

Sun

Yang

Zhang

et al. 2018

Cell Physiol Biochem

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“…Once transcribed, precursor tRNAs must fold properly to undergo maturation, which can be disrupted by sequence-altering mutations. The unique structure of tRNAs dictates processing by RNases, addition of modifications, accurate recognition by aminoacyl tRNA synthetases, incorporation into the translating ribosome, and accurate positioning of the anticodon relative to mRNA codons (21,22). Because of the need to maintain sequence specificity, DNA encoding the mature portions of tRNAs are well conserved (21).…”

Section: Significance Statementmentioning

confidence: 99%

Transfer RNA genes experience exceptionally elevated mutation rates

Thornlow

Hough

Roger

et al. 2017

Preprint

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0The authors declare no conflict of interest. 6Significance Statement 2 7 tRNAs are essential for the production of all proteins in all tissues across life and are therefore 2 8 among the most highly transcribed loci in the genome. Our study shows that the frequent 2 9 transcription of tRNAs results in a highly elevated mutation rate at tRNA loci that is between 8-3 0 and 14-fold higher for tRNAs than for the rest of the genome. We also show that the strength of 3 1 natural selection, which acts to remove sequence-altering mutations, is extremely strong in 3 2 tRNAs, but is relaxed in introns and regions flanking tRNAs. Finally, our results indicate that 3 3 mutation rates in non-functional tRNA flanking regions are similarly elevated, and levels of 3 4 genetic variation correlate strongly with expression. These observations suggest that a predictive 3 5 model could facilitate future studies of tRNA function. 6Transfer RNAs (tRNAs) play an essential role in protein synthesis across all of life. Their 3 7peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/229906 doi: bioRxiv preprint first posted online Dec. 6, 2017; primary function is in the translation of the genetic code into the corresponding amino acid 3 8 sequences that make up proteins. Thus, tRNA molecules are critical for virtually all cellular 3 9 processes, and the genes encoding tRNA molecules have been highly conserved over 4 0 evolutionary time (1). The necessity of tRNAs in large quantities also makes them among the 4 1 most highly transcribed loci in the genome. Indeed, many tRNA genes may experience greater 4 2 levels of transcription than even the most highly transcribed protein-coding genes (2, 3). Such 4 3 high levels of transcription suggest that tRNA genes may experience high levels of transcription-4 4 associated mutagenesis (TAM) compared to the rest of the genome, making the tRNA gene 4 5 family an excellent model system for studying the interplay between natural selection and 4 6 elevated mutation rates. 4 7 tRNA | transcription | mutagenesis | TAM 8Transcription affects the mutation rates of transcribed genes (4) through the unwinding and 4 9 separation of complementary DNA strands (5). In particular, during transcription, a nascent RNA 5 0 strand forms a hybrid DNA-RNA complex with a template DNA strand. While the 5 1 complementary tract of non-template DNA is temporarily isolated, it is chemically reactive and 5 2 thus accessible by potential mutagens (5). In addition, if transcription and DNA replication occur 5 3concomitantly at a particular locus, collisions between RNA Polymerase and the DNA 5 4 replication fork are possible, which may also result in damage to DNA (6). Several cellular 5 5 agents have also been shown to cause damage in highly expressed genes (7). Among the most 5 6 notable sources of mutation associated with high transcription is activation-induced cytidine 5 7 deaminase (AID) (8). AID a...

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“…A relatively underappreciated phenomenon of stress‐induced translational reprograming is cleavage of tRNAs. For a long time, these tRNA fragments were considered as degradation products but recent work highlights their role in modulating protein synthesis during cellular stress, proliferation, and differentiation . One such stress‐dependent cleavage of tRNAs is catalyzed by the ribonuclease angiogenin (ANG), which target the anticodon loop to produce tRNA halves called tRNA‐derived stress‐induced RNAs (tiRNAs).…”

Section: Reprogramming Of Protein Synthesis Under Stressmentioning

confidence: 99%

Translational Control under Stress: Reshaping the Translatome

2019

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Adequate reprogramming of cellular metabolism in response to stresses or suboptimal growth conditions involves a myriad of coordinated changes that serve to promote cell survival. As protein synthesis is an energetically expensive process, its regulation under stress is of critical importance. Reprogramming of messenger RNA (mRNA) translation involves well‐understood stress‐activated kinases that target components of translation initiation machinery, resulting in the robust inhibition of general translation and promotion of the translation of stress‐responsive proteins. Translational arrest of mRNAs also results in the accumulation of transcripts in cytoplasmic foci called stress granules. Recent studies focus on the key roles of transfer RNA (tRNA) in stress‐induced translational reprogramming. These include stress‐specific regulation of tRNA pools, codon‐biased translation influenced by tRNA modifications, tRNA miscoding, and tRNA cleavage. In combination, signal transduction pathways and tRNA metabolism changes regulate translation during stress, resulting in adaptation and cell survival. This review examines molecular mechanisms that regulate protein synthesis in response to stress.

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Roles of tRNA-derived fragments in human cancers

Cited by 116 publications

References 97 publications

tRNA-Derived Fragments as Novel Predictive Biomarkers for Trastuzumab-Resistant Breast Cancer

tRNA-Derived Fragments as Novel Predictive Biomarkers for Trastuzumab-Resistant Breast Cancer

Transfer RNA genes experience exceptionally elevated mutation rates

Translational Control under Stress: Reshaping the Translatome

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