The function of tRNA-derived fragments in cancer

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The function of tRNA-derived fragments in cancer

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The function of tRNA-derived fragments in cancer. 

tRNA-derived fragments (tRNA fragments, tRF) are non-coding RNA (ncRNA) derived from tRNA. But the production of tRF is not a random tRNA degradation product.

It is actually controlled by a set of highly conservative and precise specific cleavage mechanisms, and the final transcripts produced by these cleavage mechanisms are 14-50 nucleotides in length.

In recent years, there have been more and more researches on tRFs. Therefore, the function of tRFs can be understood.

With more and more researches on tRFs, some special functions have also been discovered.

Just recently, a review on tRF was published. So based on the content in this document, an appropriate translation is carried out. Let’s learn about the function of tRF. 

Biogenesis and discovery of tRF

Usually, we define and name tRF based on the cutting position on the precursor and mature tRNA. These tRFs can be roughly divided into four categories (👇).

1. tRNA has undergone extensive processing and a series of chemical modifications during its life cycle. During tRNA maturation, endonuclease Z (RNase Z, ELAC2) removes the 3’tail sequence from the pre-tRNA, resulting in 1-tRF.
2. 5′-tRF produced by cleavage of the 5’end in the D ring
3. 3’tRF generated by cleavage of the 3’end in the T loop
4. tRNA-derived stress-induced RNA (tRNA-derived stress-induced RNAs, tiRNA), 30-50 bases in length. It is produced by specific cleavage of angiogenin (ANG) in the anticodon loop of mature tRNA under stress conditions. Under hypoxia, starvation, viral infection, arsenite, heat shock or heavy metal-induced cellular stress/toxicity, ANG acts as a ribonuclease activated and secreted by stress, which can be transported to the cytoplasm and lyse tRNF in the cytoplasm. Into tiRNA.

In recent years, the most commonly used techniques for identifying tRF are deep sequencing and microarrays. This large-scale discovery of tRF has facilitated the development of several tRF-related databases (table below). This review summarizes the previously published databases related to tRFs.

Recently, two more databases related to tRF have been published. The specifics can be seen in our tomorrow’s post.

• tRFdb:  Display tRF sequences and read counts of 8 species including humans
• MINTbase:  A database of tRF information from nucleic acid and mitochondrial tRNA
• tRFexplorer: The expression of tRFs in each cell line in NCI-60 and each TCGA tumor type is shown.
• tRF2Cancer:  Identify tRF from a small RNA sequencing dataset of various cancer types
• OncotRF:  Provide the most comprehensive tRF resources related to human cancer, including the exploration of tRF functions and the identification of diagnostic and prognostic biomarkers

Biological functions of tRFs

Although the biological functions of tRFs are complex and need to be further clarified, our current understanding of their functions has been summarized into three categories: RNA silencing, translation regulation and epigenetic regulation (Figure 2). These three types of tRF functions have also become the focus of cancer research.

RNA silencing

Analysis using PARCLIP (Photoactivatable-Ribonucleoside Enhanced Crosslinking and Immunoprecipitation) data shows that some 5′-tRF and 3′-tRF can bind to Argonautes (AGO) in a similar manner to miRNA, but they preferentially bind to AGO1, 3, and 4.

Instead of AGO2. Most 5′-tRF and 3′-tRF have been shown to interact with RNA in cells, indicating that most tRF may play an important role in RNA interference (small interfering RNAs, RNAi)-mediated silencing.

Previous studies have observed that changes in the expression level of tRF have a significant impact on the silencing of microRNA (miRNA) and small interfering RNA (siRNA), but not on the abundance of miRNA and siRNA, which also indicates that tRF is involved in the Global regulation of small RNA silencing.

In addition, 3′-tRF reduced gene expression in HEK293T cells after transcription.

This 3′-tRF-mediated decrease in expression is Dicer-independent, but AGO-dependent, and the target is recognized by sequence complementation.

Current research shows that tRF directly targets mRNA in a manner similar to miRNA, and even competes with miRNA for binding to its target, thereby playing a role in gene silencing.

Another mechanism for tRF to silence genes is to competitively bind mRNA regulatory proteins.

For example, unlike the above-mentioned mechanism of tRF in virus infection, 1-tRF tRF_U3_1 can directly bind to La/SSB protein and inhibit La/SSB-dependent viral gene expression.

This means that tRF may be involved in many different mechanisms of the same disease.

Translation control

Although tRNA is an important part of the translation mechanism, the way in which tRF performs translation regulation is not only the result of changes in the number of mature tRNAs involved in protein synthesis.

Stress-induced 5′-tiRNAs can inhibit protein synthesis and trigger the assembly of stress granules (SGs) independent of phosphorylated elF2α.

Further studies have shown that 5′-tiRNA, such as 5′-tiRNAAla and 5′-tiRNACys, can inhibit overall translation by replacing the translation eukaryotic initiation factors eIF4G and eIF4A from mRNA and replacing eIF4F from the isolated m7G cap.

Epigenetic regulation

The expression of biological genetic information is controlled by DNA sequence and epigenetic information.

Epigenetics mainly regulates gene expression through DNA methylation, histone modification, chromatin remodeling and ncRNA regulation.

A number of studies have shown that tRF can regulate gene expression by affecting different epigenetic processes.

Transposable elements (TEs) and their repetitive sequences contribute to the formation and function of chromosomes, induce epigenetic regulation of specific genes, and drive transcription.

However, the mobility of TE is driven by a complete active transposon. The transcription of TEs is usually inhibited by epigenetic markers such as histone modification and DNA methylation.

In the absence of epigenetic transcriptional suppression, 3′-tRFs can strongly inhibit the long terminal repeat (LTR)-retroposon or endoscopy in mice by targeting the highly conserved primer binding site of the LTR-retrotransposon Source-derived retrovirus (ERV) activity.

tRF can also participate in ncRNA regulation. The tRNA methyltransferase DNMT2 limits the extent of tRNA fragmentation in the heat shock reaction.

The tRF produced can inhibit the activity of Dicer-2 on long double-stranded RNA (dsRNA).

Therefore, the heat-shocked DNMT2 mutation leads to the accumulation of dsRNA and the production of less siRNA, which leads to the dysregulation of siRNA pathway-dependent genes.

The function of tRNA-derived fragments in cancer

(source:internet, reference only)

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