tRNA-derived fragments: Mechanisms underlying their regulation of gene expression and potential applications as therapeutic targets in cancers and virus infections

Yu, Xiuchong; Xie, Yaoyao; Zhang, Shuangshuang; Song, Xuemei; Xiao, Bingxiu; Yan, Zhilong

doi:10.7150/thno.51963

Cited by 99 publications

(87 citation statements)

References 76 publications

(78 reference statements)

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“…tsRNAs have been identified as members of the gene regulatory network, which controls many key pathophysiological processes and pathogenic risk factors, such as neurodegenerative diseases, cancers, metabolic diseases, pathological stress damage, and so on [5,10,29]. Although the mechanisms of most ncRNAs in regulating diseases are still unknown [30][31][32].…”

Section: Discussionmentioning

confidence: 99%

Clinical diagnostic values of transfer RNA-derived fragment tRF-19-3L7L73JD and its effects on the growth of gastric cancer cells

Shen¹,

Xie²,

Yu³

et al. 2021

J. Cancer

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Background and aim: Medicine has made great progress, but gastric cancer is still one of the most common malignant tumors worldwide. tRNA-derived fragments (tRFs), a type of small non-coding RNA, have been found to play important roles in cancers. Due to an abundance of modifications, tRFs have the potential to serve as cancer biomarkers. However, the relationship between tRFs and gastric cancer is still largely unclear. We have identified a new tRF, tRF-19-3L7L73JD, found to be expressed at a lower level in gastric cancer patients than healthy controls. Our study aims to explore the diagnostic value of tRF-19-3L7L73JD screening in gastric cancer and to investigate its effects on the growth of gastric cancer cells. Methods: Using quantitative reverse transcription-polymerase chain reaction, we identified tRF-3L7L73JD as differentially expressed in plasma from gastric cancer patients compared to healthy controls. We measured tRF-3L7L73JD levels in plasma from 40 gastric cancer patients and healthy controls. Furthermore, we tested another cohort containing 89 gastric cancer patients and 98 healthy controls to validate our findings. Next, we analyzed the relationship between levels of tRF-19-3L7L73JD in plasma and clinicopathological data of gastric cancer patients, and then evaluated the effects of tRF-19-3L7L73JD on gastric cancer cell growth. Cell proliferation was measured by the Cell Counting Kit-8 and clone formation experiments after transfer with tRF-19-3L7L73JD mimics. The changes in cell migration ability were explored through the scratch and Transwell experiments. Finally, we explored changes in apoptosis and cell cycle by flow cytometry. Results: tRF-19-3L7L73JD showed lower expression in the tested gastric cancer patients. In the validation cohort tRF-19-3L7L73JD was also expressed at low levels in the pre-operative plasma group compared with healthy plasma and post-operative plasma groups. Additionally, a comparison of gastric cancer cell lines with normal gastric epithelial cell lines produced the same result. We found that tRF-19-3L7L73JD expression in patients was related to tumor size. The area under the curve (AUC) was 0.6230, with sensitivity and specificity of 0.4045 and 0.7959, respectively. Cellular function studies revealed that tRF-19-3L7L73JD inhibited cell proliferation and migration, induced apoptosis, and arrested cells at G0/G1 phases, suggesting it may suppress the development of gastric cancer. Conclusion:The results suggest that tRF-19-3L7L73JD may be useful as a biomarker of gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Clinical diagnostic values of transfer RNA-derived fragment tRF-19-3L7L73JD and its effects on the growth of gastric cancer cells

Shen¹,

Xie²,

Yu³

et al. 2021

J. Cancer

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“…tRFs are derived from mature tRNAs or pre-tRNAs. According to their corresponding positions on tRNAs, tRFs can further be divided into four types including tRF-5, tRF-3, tRF-1, and tRF-2 ( Kumar et al, 2015 ; Yu et al, 2021 ). tRF-5 corresponds to the 5′ end of mature tRNAs and cutting occurs in the D-loop.…”

Section: Discussionmentioning

confidence: 99%

“…tRF-1 is derived from the 3′ tail sequence of the precursor tRNA, which contains a poly U sequence at the 3′ end. tRF-2, not belonging to tRF-5, tRF-3, or tRF-1, comes primarily from the intermediate region of mature tRNAs ( Goodarzi et al, 2015 ; Wang et al, 2020 ; Yu et al, 2021 ). tRFs & tiRNAs play biological roles through a variety of mechanisms, including interacting with proteins or mRNAs, regulating gene expression, controlling cell cycle, regulating chromatin and epigenetic modifications ( Guzzi et al, 2018 ; Xie et al, 2020 ; Li et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Differential Expression Profiles and Function Predictions for tRFs & tiRNAs in Skin Injury Induced by Ultraviolet Irradiation

Fang

Liu

Yan

et al. 2021

Front. Cell Dev. Biol.

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Ultraviolet (UV) radiation is a major environmental factor contributing skin damage. As UV exposure is inevitable, it is necessary to pay attention to the underlying molecular mechanisms of UV-induced skin damage to develop effective therapies. tRNA-derived stress-induced RNAs (tiRNAs) and tRNA-derived fragments (tRFs) are tRNA-derived small RNAs (tsRNAs) that are a novel class of short, non-coding RNAs. However, the functions behind tRFs & tiRNAs in UV-induced skin injury are not yet clear. Firstly, the animal model of ultraviolet irradiation induced skin damage was established. Then the skin samples were preserved for the follow-up experiment. Sequencing was used to screen expression profiles and predict target genes. Compared with normal skin, a total of 31 differentially expressed tRFs & tiRNAs were screened. Among these, 10 tRFs & tiRNAs were shown to be significantly different in expression levels, where there were 4 up-regulated and 6 down-regulated target genes. Bioinformatics analyses revealed potential up-regulated tsRNAs (tRF-Val-AAC-012, tRF-Pro-AGG-012, tRF-Val-CAC-018, tRF-Val-AAC-031) and down-regulated tsRNAs (tRF-Arg-CCT-002, tRF-Trp-TCA-001, tiRNA-Ser-GCT-001, tRF-Gly-CCC-019, tRF-Ala-TGC-001, tRF-Ala-TGC-002). In summary, it was speculated that tRF-Gly-CCC-019 plays an important role in acute skin injury induced by UVB radiation by regulating the ras-related C3 botulinum toxin substrate 1 (Rac1) gene in the WNT signaling pathway. This study provides new insights into the mechanisms and therapeutic targets of UV-induced skin injury.

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“…In addition, the cleavage of tRNAs by RNases would probably be modulated by the presence of regulatory proteins within the cell [60]. For example, Onconase selectivity for specific tRNAs was attributed to the presence in vivo of RNA binding proteins that might protect RNA regions from RNase activity [52,61].…”

Section: Discussionmentioning

confidence: 99%

Selective cleavage of ncRNA and antiviral activity by human RNase2/EDN in a macrophage infection model

Wei

et al. 2021

Preprint

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RNase2, also named the Eosinophil derived Neurotoxin (EDN), is one of the main proteins secreted by the eosinophil secondary granules. RNase2 is also expressed in other leukocyte cells and is the member of the human ribonuclease A family most abundant in macrophages. The protein is endowed with a high ribonucleolytic activity and participates in the host antiviral activity. Although RNase2 displays a broad antiviral activity, it is mostly associated to the targeting of single stranded RNA viruses. To explore RNase2 mechanism of action in antiviral host defence we knocked out RNase2 expression in the THP1 monocyte cell line and characterized the cell response to human Respiratory Syncytial Virus (RSV). We observed that RSV infection induced the RNase2 expression and protein secretion in THP1 macrophage-derived cells, whereas the knockout (KO) of RNase2 resulted in higher RSV burden and reduced cell viability. Next, by means of the cP-RNAseq methodology, which uniquely amplifies the RNA 2'3'cyclic-phosphate-end products released by an endonuclease cleavage, we compared the ncRNA population in native and RNase2-KO cell lines. Among the ncRNAs accumulated in WT versus KO cells, we found mostly tRNA-derived fragments and secondly miRNAs. Analysis of the differential sequence coverage of tRNAs molecules in native and KO cells identified fragments derived from only few parental tRNAs, revealing a predominant cleavage at anticodon loops and secondarily at D-loops. Inspection of cleavage region identified U/C and A, at 5' and 3' sides of cleavage sites respectively (namely RNase B1 and B2 base binding subsites). Likewise, only few selected miRNAs were significantly more abundant in WT versus RNase2-KO cells, with cleavage sites located at the end of stem regions with predominance for pyrimidines at B1 but following an overall less defined nucleotide specificity. Complementarily, by screening of a tRF/tiRNA PCR array we identified an enriched population of tRNA-derived fragments associated to RNase2 expression and RSV infection. The present results confirm the contribution of the protein in macrophage response against virus infection and provide the first evidence of its cleavage selectivity against ncRNA population. A better understanding of the mechanism of action of RNase2 recognition of cellular RNA during the antiviral host defence should pave the basis for the design of novel antiviral drugs.

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tRNA-derived fragments: Mechanisms underlying their regulation of gene expression and potential applications as therapeutic targets in cancers and virus infections

Cited by 99 publications

References 76 publications

Clinical diagnostic values of transfer RNA-derived fragment tRF-19-3L7L73JD and its effects on the growth of gastric cancer cells

Clinical diagnostic values of transfer RNA-derived fragment tRF-19-3L7L73JD and its effects on the growth of gastric cancer cells

Differential Expression Profiles and Function Predictions for tRFs & tiRNAs in Skin Injury Induced by Ultraviolet Irradiation

Selective cleavage of ncRNA and antiviral activity by human RNase2/EDN in a macrophage infection model

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