Transfer RNA halves (tRHs) have multiple biological functions. However, the biogenesis of specific 5'-tRHs under certain conditions is currently unclear to researchers. Recently, in a research report titled "5'-tRNAGly(GCC) halves generated by IRE1α are linked to the ER stress response" published in the international journal Nature Communications, scientists from Yanbian University and other institutions in China revealed the synthesis process and key role of the transfer RNA-derived fragment 5'-tRH-GlyGCC in cancer progression. By interacting with splicing factors, it may be able to regulate gene expression, alternative splicing, and messenger RNA processing.
Transfer RNA-derived fragments (tRFs) are small molecules present in most organisms. When certain tRFs are cleaved by enzymes at specific sites, tRHs or tRNA halves are produced. Although tRFs can play a variety of biological functions, researchers know little about the process of their synthesis. To fill this knowledge gap, researchers have tried to analyze the biogenesis and function of specific tRFs such as tRHs. The relevant research results may provide new hope for later scientists to develop new cancer therapies and introduce potential biomarkers to improve clinical treatment outcomes.
The inspiration for this study came from an accidental discovery by researchers in 2010. At that time, they found that high levels of small RNA fragments in ovarian cancer samples were derived from specific tRNAs, not the expected microRNAs. At that time, the physiological role of tRNA fragments was not clear to researchers. So they felt it was necessary to further investigate and understand the role of these fragments in the process of cancer occurrence. In order to investigate the key role played by the special fragment 5'-tRH-GlyGCC in cancer, the researchers combined cutting-edge molecular and biochemical techniques to conduct relevant research.
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They used nanopore sequencing to analyze transcriptomic features and performed alternative splicing experiments to assess how RNA fragments affect gene expression. In addition, they carefully analyzed the interaction between 5'-tRH-GlyGCC and heterogeneous nuclear ribonucleoproteins involved in the splicing process. At the same time, the researchers conducted in vitro experiments to analyze the proliferation of cancer cells and used in vivo xenograft mouse models to evaluate the therapeutic potential of targeting 5'-tRH-GlyGCC.
The researchers found that under endoplasmic reticulum pressure, inositol-requiring enzyme 1α (IRE1α) can cleave tRNAGly (GCC) to produce 5'-tRH-GlyGCC. In addition, the findings indicate that 5'-tRH-GlyGCC plays a key role in alternative splicing and messenger RNA isoform regulation, thereby affecting the expression of genes involved in cancer progression. The researchers found that the RNA fragment interacts with the HNRNP protein that regulates the splicing process. In vitro experimental results show that regulating the level of 5'-tRH-GlyGCC may significantly affect cancer cell proliferation. Professor Lee said, "Our research solves a long-standing question in RNA and cancer biology. Now we have revealed how specialized tRNA fragments are generated and how they play an important role in cellular stress and cancer. This This may provide new opportunities for the development of new diagnostic and therapeutic applications in the future."
Figure 1. Proposed model for the IRE1α selective generation of 5'-tRH-GlyGCC that contributes to cellular adaptation upon ER stress presented in diverse eukaryotic organisms from yeast to humans. (Jin H, et al., 2024)
In xenograft mouse models, inhibiting this RNA fragment using antisense oligonucleotides (ASOs) may lead to tumor regression. These findings suggest that 5'-tRH-GlyGCC may serve as a special biomarker for early-stage cancer detection. Because its levels can be easily detected in blood samples by RT-PCR, similar to the detection of coronavirus. Additionally, its role in tumor growth may make it a promising target for therapeutic intervention.
"Blocking these tRNA fragments will lead to tumor regression in mouse models. Now we are further exploring how to transport ASOs into human cells, which will bring us one step closer to clinical application." Researcher Lee explained. Research in this article It was emphasized that 5'-tRH-GlyGCC may serve as a special biomarker for cancer and its potential as a therapeutic target was explored. Along with very promising therapeutic results from antisense oligonucleotide therapies, this discovery could pave the way for breakthroughs in cancer therapy.
Reference
Jin H, et al. 5'-tRNAGly (GCC) halves generated by IRE1α are linked to the ER stress response. Nature communications, 2024, 15(1): 9273.