Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA-derived small RNAs

Chen, Zhuojia; Qi, Meijie; Shen, Bin; Luo, Guan‐Zheng; Wu, Yinuo; Li, Jiexin; Lu, Zhike; Zheng, Zhong; Dai, Qing; Wang, Hongsheng

doi:10.1093/nar/gky1250

Cited by 235 publications

(184 citation statements)

References 53 publications

Supporting

Mentioning

177

Contrasting

Order By: Relevance

“…The latter is consistent with the induction of a 5' half from tRNA His by poly(I:C) treatment on cell lines through RNaseL action [76], an enzyme that is responsive to bacteria and virus infection [77][78][79] and has been suggested to balance between neuroprotective and neurotoxic functions of microglia [80]. Since tRNA half levels can be regulated by tRNA level, tRNA cleavage, tRNA modification and tRNA half stability [81][82][83][84][85][86], it will be interesting to examine how each factor contributes to the regulation observed in the maternal-fetal interface.…”

Section: Discussionsupporting

confidence: 72%

tRNA-derived fragments and microRNAs in the maternal-fetal interface of a mouse maternal-immune-activation autism model

Frost

Lammert

et al. 2019

Preprint

View full text Add to dashboard Cite

tRNA-derived small fragments (tRFs) and tRNA halves have emerging functions in different biological pathways, such as regulating gene expression, protein translation, retrotransposon activity, transgenerational epigenetic changes and response to environmental stress. However, small RNAs like tRFs and microRNAs in the maternal-fetal interface during gestation have not been studied extensively. Here we investigated the small RNA composition of mouse placenta/decidua, which represents the interface where the mother communicates with the fetus, to determine whether there are specific differences in tRFs and microRNAs during fetal development and in response to maternal immune activation (MIA). Global tRF expression pattern, just like microRNAs, can distinguish tissue types among placenta/decidua, fetal brain and fetal liver. In particular, 5' tRNA halves from tRNA Gly , tRNA Glu , tRNA Val and tRNA Lys are abundantly expressed in the normal mouse placenta/decidua. Moreover, tRF and microRNA levels in the maternal-fetal-interface change dynamically over the course of embryonic development. To see if stress alters non-coding RNA expression at the maternal-fetal interface, we treated pregnant mice with a viral infection mimetic, which has been shown to promote autism-related phenotypes in the offspring. Acute changes in the levels of specific tRFs and microRNAs were observed 3-6 hours after MIA and are suppressed thereafter. A group of 5' tRNA halves is down-regulated by MIA, whereas a group of 18-nucleotide tRF-3a is up-regulated. In conclusion, tRFs show tissue-specificity, developmental changes and acute response to environmental stress, opening the possibility of them having a role in the fetal response to MIA.

show abstract

Section: Discussionsupporting

confidence: 72%

tRNA-derived fragments and microRNAs in the maternal-fetal interface of a mouse maternal-immune-activation autism model

Frost

Lammert

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Indeed, Alkbh1 is not the sole tRNA m 1 A demethylase. Recently, Alkbh3, another member of the same family, was shown to also demethylate m 1 A and impact tRNA stability 26 . However, CLIP-seq data showed a different affinity patterns for tRNA species for both enzymes 17,26 .…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Alkbh3, another member of the same family, was shown to also demethylate m 1 A and impact tRNA stability 26 . However, CLIP-seq data showed a different affinity patterns for tRNA species for both enzymes 17,26 . Moreover, other tRNA modifications impact stability of tRNA and were not addressed in our work 11,27,28 .…”

Section: Discussionmentioning

confidence: 99%

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

Rashad

Han

Sato

et al. 2020

Preprint

View full text Add to dashboard Cite

tiRNAs are small non-coding RNAs produced when tRNA is cleaved under stress. tRNA methylation modifications has emerged in recent years as important regulators for tRNA structural stability and sensitivity to cleavage and tiRNA generation during stress, however, the specificity and higher regulation of such a process is not fully understood. Alkbh1 is a m 1 A demethylase that leads to destabilization of tRNA and enhanced tRNA cleavage. We examined the impact of Alkbh1 targeting via gene knockdown or overexpression on B35 rat neuroblastoma cell line fate following stresses and on tRNA cleavage. We show that Alkbh1 impact on cell fate and tRNA cleavage is a stress specific process that is impacted by the demethylating capacity of the cellular stress in question. We also show that not all tRNAs are cleaved equally following Alkbh1 manipulation and stress, and that Alkbh1 KD fails to rescue tRNAs from cleavage following demethylating stresses. These findings shed a light on the specificity and higher regulation of tRNA cleavage and should act as a guide for future work exploring the utility of Alkbh1 as a therapeutic target for cancers or ischemic insult.

show abstract

“…After 24hr transfected by Cas13b/PspCas13b-fusion and gRNA plasmids, total RNA was harvested and extracted by Trizol (Invitrogen) according to the protocol used in our previous study 42 . Extracted total RNA were quantified and reverse transcribed into cDNA using the PrimeScript RT Reagent Kit (TaKaRa).…”

Section: Total Rna Isolation and Quantitative Pcrmentioning

confidence: 99%

Targeted mRNA demethylation using an engineered dCas13b-ALKBH5 fusion protein

Chen

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

AbstractStudies on biological functions ofN6-methyladenosine (m6A) modification in mRNA have sprung up in recent years. Here we construct and characterize a CRISPR-Cas13b-based tool for the first time that targeted m6A methylation of mRNA by fusing the catalytically dead Type VI-B Cas13 enzyme from Prevotella sp.P5-125 (dPspCas13b) with the m6A demethylase ALKBH5, which is named as dm6ACRISPR. Subsequently, such system is shown to specific demethylase the m6A of target mRNA such as CYB5A to increase its mRNA stability. In addition, the dm6ACRISPR system appeared to afford efficient demethylation of the target genes with tenuous off-target effects. Together, we provide a programmable andin vivomanipulation tool to study mRNA modification and its potential biological functions of specific gene.

show abstract

Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA-derived small RNAs

Cited by 235 publications

References 53 publications

tRNA-derived fragments and microRNAs in the maternal-fetal interface of a mouse maternal-immune-activation autism model

tRNA-derived fragments and microRNAs in the maternal-fetal interface of a mouse maternal-immune-activation autism model

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

Targeted mRNA demethylation using an engineered dCas13b-ALKBH5 fusion protein

Contact Info

Product

Resources

About