Transfer RNA-derived small RNAs in the cancer transcriptome.

Darrell Green,William D Fraser,Tamas Dalmay

doi:10.1007/s00424-016-1822-9

Abstract

The cellular lifetime includes stages such as differentiation, proliferation, division, senescence and apoptosis. These stages are driven by a strictly ordered process of transcription dynamics. Molecular disruption to RNA polymerase assembly, chromatin remodelling and transcription factor binding through to RNA editing, splicing, post-transcriptional regulation and ribosome scanning can result in significant costs arising from genome instability. Cancer development is one example of when such disruption takes place. RNA silencing is a term used to describe the effects of post-transcriptional gene silencing mediated by a diverse set of small RNA molecules. Small RNAs are crucial for regulating gene expression and microguarding genome integrity. RNA silencing studies predominantly focus on small RNAs such as microRNAs, short-interfering RNAs and piwi-interacting RNAs. We describe an emerging renewal of interest in a ‘larger’ small RNA, the transfer RNA (tRNA). Precisely generated tRNA-derived small RNAs, named tRNA halves (tiRNAs) and tRNA fragments (tRFs), have been reported to be abundant with dysregulation associated with cancer. Transfection of tiRNAs inhibits protein translation by displacing eukaryotic initiation factors from messenger RNA (mRNA) and inaugurating stress granule formation. Knockdown of an overexpressed tRF inhibits cancer cell proliferation. Recovery of lacking tRFs prevents cancer metastasis. The dual oncogenic and tumour-suppressive role is typical of functional small RNAs. We review recent reports on tiRNA and tRF discovery and biogenesis, identification and analysis from next-generation sequencing data and a mechanistic animal study to demonstrate their physiological role in cancer biology. We propose tRNA-derived small RNA-mediated RNA silencing is an innate defence mechanism to prevent oncogenic translation. We expect that cancer cells are percipient to their ablated control of transcription and attempt to prevent loss of genome control through RNA silencing.

Highlights

Transcription is a core step in the regulation of gene expression
Nonstress-induced transfer RNA (tRNA)-derived small RNAs are thought to arise from ribonucleolytic processing of tRNAs by Dicer and RNase Z [4, 20]
These classes are defined by the position of the tRNA cleavage site that gives rise to the small RNAs

Summary

Introduction

Transcription is a core step in the regulation of gene expression. It is of fundamental importance in maintaining organism function and integrity. Reports show that in organisms undergoing rapid change—for example during development or in response to periodic external perturbations such as sexual reproduction—miRNAs can switch from gene regulators to molecular guards [7, 11, 17] In this latter role, miRNAs may buffer against abrupt fluctuations in mRNA transcription (Fig. 2). This can be important to prevent deleterious effects of variation of mRNA transcript abundance and minimising genetic instability leading to molecular-based disorders Due to their major role in modifying gene expression, miRNAs have been the focus of many cancer studies. It was proposed that tiRNAs and tRFs could have roles in cancer progression, similar to the role of miRNAs. As hypoxia is a major stress encountered by cancer cells, tRNA-derived small RNAs induced under hypoxic conditions may act to curb metastatic progression [10]. The lack of luciferase activity from reporters fused with CD97 and TIMP3 is direct evidence of tRF-mediated displacement of oncogenic transcripts from YBX1 [10]

Summary and conclusions

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