The stress specific impact of ALKBH1 on tRNA cleavage and tiRNA generation

Rashad, Sherif; Han, Xiaobo; Sato, Kanako; Mishima, Eikan; Abe, Takaaki; Tominaga, Teiji; Niizuma, Kuniyasu

doi:10.1101/2020.01.31.928234

Cited by 5 publications

(19 citation statements)

References 31 publications

(25 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although previous studies showed that the production of tiRNAs is closely related to ANG [27,36,37], a recent study verified that the production of tiRNA is not completely dependent on ANG, suggesting there are other RNases that produce tiRNAs [38]. Moreover, mature tRNA has a lot of base modifications, such as m5C, m1A, m3C, and Ψ (Pseudouridylation), which can protect tRNAs from cleavage [39][40][41][42][43]. It is also essential to understand the intrinsic and extrinsic factors that participate in the production of tsRNAs.…”

Section: Discussionmentioning

confidence: 99%

A specific tRNA half, 5’tiRNA-His-GTG, responds to hypoxia via the HIF1α/ANG axis and promotes colorectal cancer progression by regulating LATS2

Tao

Wang

Cheng

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background Currently, tRNA-derived small RNAs (tsRNAs) are recognized as a novel and potential type of non-coding RNAs (ncRNAs), which participate in various cellular processes and play an essential role in cancer progression. However, tsRNAs involvement in colorectal cancer (CRC) progression remains unclear. Methods Sequencing analyses were performed to explore the tsRNAs with differential expression in CRC. Gain- and loss-of functions of 5’tiRNA-His-GTG were performed in CRC cells and xenograft tumor to discover its role in the progression of CRC. Hypoxia culture and hypoxia inducible factor 1 subunit alpha (HIF1α) inhibitors were performed to uncover the biogenesis of 5’tiRNA-His-GTG. The regulation of 5’tiRNA-His-GTG for large tumor suppressor kinase 2 (LATS2) were identified by luciferase reporter assay, western blot, and rescue experiments. Results Here, our study uncovered the profile of tsRNAs in human CRC tissues and confirmed a specific tRNA half, 5’tiRNA-His-GTG, is upregulated in CRC tissues. Then, in vitro and in vivo experiments revealed the oncogenic role of 5’tiRNA-His-GTG in CRC and found that targeting 5’tiRNA-His-GTG can induce cell apoptosis. Mechanistically, the generation of 5’tiRNA-His-GTG seems to be a responsive process of tumor hypoxic microenvironment, and it is regulated via the HIF1α/angiogenin (ANG) axis. Remarkably, LATS2 was found to be an important and major target of 5’tiRNA-His-GTG, which renders 5’tiRNA-His-GTG to “turn off” hippo signaling pathway and finally promotes the expression of pro-proliferation and anti-apoptosis related genes. Conclusions In summary, the findings revealed a specific 5’tiRNA-His-GTG-engaged pathway in CRC progression and provided clues to design a novel therapeutic target in CRC.

show abstract

Section: Discussionmentioning

confidence: 99%

A specific tRNA half, 5’tiRNA-His-GTG, responds to hypoxia via the HIF1α/ANG axis and promotes colorectal cancer progression by regulating LATS2

Tao

Wang

Cheng

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…However, recent studies have identified Ang‐independent cleavage (Y. Akiyama et al, 2019; Krishna et al, 2019; Su et al, 2019). In addition, we observed in our previous report the existence of larger 5ʹ tiRNA fragments implying cleavage away from the anticodon site (i.e., noncanonical cleavage; Rashad, Han, et al, 2020). The exact role of these noncanonical fragments is not yet known, as well as their regulation and cleavage patterns.…”

Section: Introductionmentioning

confidence: 63%

“…The same process was shown to drive metastasis in breast cancer (Goodarzi et al, 2015). tRNA modifications play an important role in regulating transcript availability and efficient protein translation (Liu et al, 2016; Pollo‐Oliveira et al, 2020) and can impact cellular stress response (Rashad, Han, et al, 2020) and cancer biology (Rossello‐Tortella et al, 2020). tRNA is also a source of small noncoding RNAs that have an important regulatory role in translation, namely, tiRNAs and tRFs (tRNA‐derived fragments produced via DICER; Ivanov et al, 2011; Rashad, Niizuma, et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Do these fragments play a role beyond the protein translation repressing role of tiRNAs is still an open question (Emara et al, 2010; Ivanov et al, 2011, 2014; Rashad, Niizuma, et al, 2020). The cleavage process of tRNA was shown to be regulated, at least at some level, via tRNA methylation modifications such as 1‐methyadenosine (m 1 A) modifications and 5‐methylcytosine (m 5 C) modifications via a variety of tRNA methyltransferases or demethylases (Chen et al, 2019; Kawarada et al, 2017; Liu et al, 2016; Rashad, Han, et al, 2020; Tuorto et al, 2012). We recently reported that Alkbh1, a cytosolic and mitochondrial tRNA m 1 A demethylase, regulates cellular stress responses and tRNA cleavage in a stress‐specific manner (Rashad, Han, et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…The cleavage process of tRNA was shown to be regulated, at least at some level, via tRNA methylation modifications such as 1‐methyadenosine (m 1 A) modifications and 5‐methylcytosine (m 5 C) modifications via a variety of tRNA methyltransferases or demethylases (Chen et al, 2019; Kawarada et al, 2017; Liu et al, 2016; Rashad, Han, et al, 2020; Tuorto et al, 2012). We recently reported that Alkbh1, a cytosolic and mitochondrial tRNA m 1 A demethylase, regulates cellular stress responses and tRNA cleavage in a stress‐specific manner (Rashad, Han, et al, 2020). This indicates a higher‐level regulation rather than a global nonspecific cleavage pattern, since not all tRNA species are equally modified (Chen et al, 2019; Kawarada et al, 2017; Liu et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The cell and stress‐specific canonical and noncanonical tRNA cleavage

Rashad

Tominaga

Niizuma

2020

Journal Cellular Physiology

Self Cite

View full text Add to dashboard Cite

Following stress, transfer RNA (tRNA) is cleaved to generate tRNA halves (tiRNAs). These tiRNAs have been shown to repress protein translation. Angiogenin was considered the main enzyme that cleaves tRNA at its anticodon to generate 35–45 nucleotide long tiRNA halves, however, the recent reports indicate the presence of angiogenin‐independent cleavage. We previously observed tRNA cleavage pattern occurring away from the anticodon site. To explore this noncanonical cleavage, we analyze tRNA cleavage patterns in rat model of ischemia–reperfusion and in two rat cell lines. In vivo mitochondrial tRNAs were prone to this noncanonical cleavage pattern. In vitro, however, cytosolic and mitochondrial tRNAs could be cleaved noncanonically. Our results show an important regulatory role of mitochondrial stress in angiogenin‐mediated tRNA cleavage. Neither angiogenin nor RNH1 appear to regulate the noncanonical tRNA cleavage. Finally, we verified our previous findings of the role of Alkbh1 in regulating tRNA cleavage and its impact on noncanonical tRNA cleavage.

show abstract

Origins and evolving functionalities of tRNA-derived small RNAs

Chen

Zhang

Shi

et al. 2021

Trends in Biochemical Sciences

109

View full text Add to dashboard Cite

Transfer RNA (tRNA)-derived small RNAs (tsRNAs) are among the most ancient small RNAs in all domains of life and are generated by the cleavage of tRNAs. Emerging studies have begun to reveal the versatile roles of tsRNAs in fundamental biological processes, including gene silencing, ribosome biogenesis, retrotransposition, and epigenetic inheritance, which are rooted in tsRNA sequence conservation, RNA modifications, and protein-binding abilities. We summarize the mechanisms of tsRNA biogenesis and the impact of RNA modifications, and propose how thinking of tsRNA functionality from an evolutionary perspective urges the expansion of tsRNA research into a wider spectrum, including cross-tissue/cross-species regulation and harnessing of the 'tsRNA code' for precision medicine. On the ancientness of tsRNAs/tRNAsWith the wide application of high-throughput RNA sequencing (RNA-seq), tRNA-derived small RNAs (tsRNAs) (also called tDRs or tRNA-derived fragments, tRFs) are increasingly recognized as an emerging class of functional small noncoding RNAs (sncRNAs) in various fundamental biological and disease conditions [1,2]. tsRNAs have been identified in a wide range of species across all three domains of life, including Archaea, Bacteria, and some unicellular organisms (e.g., Protozoa), where other specialized small RNA pathways, such as miRNAs, siRNAs, and Piwi-interacting RNAs (piRNAs), are lacking [3][4][5][6][7]. These observations have positioned tsRNAs among the most ancient classes of sncRNAs for intra-and intercellular functionality and communication that may pre-date the emergence of more specialized sncRNAs. Highlights tRNA-derived small RNAs (tsRNAs) are present across all three domains of life: Archaea, Bacteria, and Eukarya.

show abstract

The stress specific impact of ALKBH1 on tRNA cleavage and tiRNA generation

Cited by 5 publications

References 31 publications

A specific tRNA half, 5’tiRNA-His-GTG, responds to hypoxia via the HIF1α/ANG axis and promotes colorectal cancer progression by regulating LATS2

A specific tRNA half, 5’tiRNA-His-GTG, responds to hypoxia via the HIF1α/ANG axis and promotes colorectal cancer progression by regulating LATS2

The cell and stress‐specific canonical and noncanonical tRNA cleavage

Origins and evolving functionalities of tRNA-derived small RNAs

Contact Info

Product

Resources

About