tRNA-derived small RNA (tsRNA or tRF)

tRNA is essential for delivering amino acid to a growing polypeptide chains.

Beyond its canonical function such as protein synthesis, tRNA performs noncanonical function by producing shorter tRNA fragments, which is called as tRNA-derived small RNA (tsRNA) or tRNA-derived fragment (tRF). It's implicated in various cancers and neurological disorders by regulating diverse cellular processes. However, their detialed mechanisms are not understood well. According to the cleavage position, tsRNA is classified into more than six subtypes.

One of the distinct function of tsRNAs is to be related to protein syntheis. Some of tsRNAs (tiRNA) are induced under various stresses and inhibit global translation. However, 22 nt LeuCAG3'tsRNA was reported to enhance target mRNA translation by unwinding duplexed target sites in the mRNA during translation (Kim et al., Nature 2017)

tsRNA-mediated translational Regulation

LeuCAG3'tsRNA binds to ribosomal protein S28 (RPS28) mRNA and unwinds the target sites in RPS28 mRNA during translation. RPS28 is required for ribosomal RNA biogenesis and a component of ribosome. Therefore, inhibition of the LeuCAG3'tsRNA decreases the cell viability and reduces the tumor growth from patient-derived hepatocellular carcinoma in mice (Kim et al. Nature. 2017) Our goal is to understand the detailed mechanism by which the tsRNA regulates mRNA translation and the tsRNA selects target sites.

The role of tsRNAs in cancer progression

Hypoxia is one of the fundamental features of solid tumors and is a critical microenvironmental stress affecting malignant progression and resistance to chemotherapy and radiation therapy. Long tsRNAs were induced in mammalian cells under hypoxia and another tsRNAs with heterogenous length are up-regulated under hypoxia, destabilizing multiple oncogenic transcripts in breast cancer cells, while highly metastatic cells evade this tumor suppressive pathway. However, hypoxia-responsive short tsRNAs have not been yet reported. Our goal is to identify the role of tsRNA in cancer progression under hypoxia and develope these tsRNAs as biomarkers or therpeutic targets.

Therapeutic applications

We will analyze the expression of the tsRNA in various patient tumor tissues using a nanopore sequencing and demethylase deep sequencing to overcome the modifications on tsRNA which interfere with cDNA synthesis required for the standard high-throughput sequencing. This approach will provide more information on the stage of cancer in which the tsRNA is expressed and the importance of prognosis. The potential of a therapeutic target will also be examined in 3D cell culture derived from PDX (patient-derived xenograft) or PDX models in mice.