New substrates and determinants for tRNA recognition of RNA methyltransferase DNMT2/TRDMT1

Li, Huari; Zhu, Deguang; Wu, Jian; Ma, Yanwei; Cai, Chao; Chen, Yong; Qin, Mian; Dai, Hanchuan

doi:10.1080/15476286.2021.1930756

Cited by 22 publications

(15 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in that study, the enzyme concentration used was extremely high, and the time taken to measure the enzymatic activity was quite long, at 70 min ( 57 ). What is more, there was no confirmation of whether the modification is indeed m 5 C after that long incubation in such an high concentration of the enzyme, especially for the new tRNA substrates ( 57 ). Based on these observations, we prefer to believe that our enzymatic assay system of hDNMT2 is closer to the in vivo system, and our result of substrate specificity of hDNMT2 is consistent with the high-throughput sequencing data ( 8 ).…”

Section: Discussionmentioning

confidence: 93%

“…During the submission of our work, another in vitro biochemical study of hDNMT2 was published, demonstrating new tRNA substrates besides tRNA Gly (GCC), tRNA Asp (GUC) and tRNA Val (AAC) ( 57 ), which is not consistent with the RNA bisulfite sequencing from Hela cells ( 8 ). However, in that study, the enzyme concentration used was extremely high, and the time taken to measure the enzymatic activity was quite long, at 70 min ( 57 ). What is more, there was no confirmation of whether the modification is indeed m 5 C after that long incubation in such an high concentration of the enzyme, especially for the new tRNA substrates ( 57 ).…”

Section: Discussionmentioning

confidence: 93%

See 1 more Smart Citation

Position 34 of tRNA is a discriminative element for m5C38 modification by human DNMT2

Huang

Xiong

et al. 2021

Nucleic Acids Research

View full text Add to dashboard Cite

Dnmt2, a member of the DNA methyltransferase superfamily, catalyzes the formation of 5-methylcytosine at position 38 in the anticodon loop of tRNAs. Dnmt2 regulates many cellular biological processes, especially the production of tRNA-derived fragments and intergenerational transmission of paternal metabolic disorders to offspring. Moreover, Dnmt2 is closely related to human cancers. The tRNA substrates of mammalian Dnmt2s are mainly detected using bisulfite sequencing; however, we lack supporting biochemical data concerning their substrate specificity or recognition mechanism. Here, we deciphered the tRNA substrates of human DNMT2 (hDNMT2) as tRNAAsp(GUC), tRNAGly(GCC) and tRNAVal(AAC). Intriguingly, for tRNAAsp(GUC) and tRNAGly(GCC), G34 is the discriminator element; whereas for tRNAVal(AAC), the inosine modification at position 34 (I34), which is formed by the ADAT2/3 complex, is the prerequisite for hDNMT2 recognition. We showed that the C32U33(G/I)34N35 (C/U)36A37C38 motif in the anticodon loop, U11:A24 in the D stem, and the correct size of the variable loop are required for Dnmt2 recognition of substrate tRNAs. Furthermore, mammalian Dnmt2s possess a conserved tRNA recognition mechanism.

show abstract

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 93%

Position 34 of tRNA is a discriminative element for m5C38 modification by human DNMT2

Huang

Xiong

et al. 2021

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

“…The reason for these rather contradictory results are still not entirely clear, but there are several possibilities: 1) DNMT1 and DNMT3a/b may also directly influence gene expression in a way that does not require the C-terminal catalytic domain ( Espada et al, 2011 ) or by interacting with recruit histone deacetylases and histone methyltransferase ( Milutinovic et al, 2004 ). 2) DNMT2, which is also known as transfer RNA (tRNA) aspartic acid methyltransferase 1 (TRDMT1) is suggested to have more activity on tRNA than DNA ( Kaiser et al, 2017 ; Li et al, 2021 ), which may serve to stabilize specific tRNAs and conduct positive post-transcription regulation of aspartic acid-rich proteins instead of gene silencing. 3) DNMTs are suggested to be involved in many methylation-independent functions, for instance, the DNA damage repair (DDR) system, which are crucial for cancer cell survival.…”

Section: Discussionmentioning

confidence: 99%

Leptin Receptor Overlapping Transcript (LEPROT) Is Associated with the Tumor Microenvironment and a Prognostic Predictor in Pan-Cancer

et al. 2021

Front. Genet.

View full text Add to dashboard Cite

Background:Leptin receptor overlapping transcript (LEPROT) is reported to be involved in metabolism regulation and energy balance as well as molecular signaling of breast cancer and osteosarcoma. LEPROT is expressed in various tissue and is suggested to be involved in cancer developments but with contradictory roles. The comprehensive knowledge of the effects of LEPROT on cancer development and progression across pan-cancer is still missing.Methods:The expressions of LEPROT in cancers were compared with corresponding normal tissues across pan-cancer types. The relationships between expression and methylation of LEPROT were then demonstrated. The correlations of LEPROT with the tumor microenvironment (TME), including immune checkpoints, tumor immune cells infiltration (TII), and cancer-associated fibroblasts (CAFs), were also investigated. Co-expression analyses and functional enrichments were conducted to suggest the most relevant genes and the mechanisms of the effects in cancers for LEPROT. Finally, the correlations of LEPROT with patient survival and immunotherapy response were explored.Results:LEPROT expression was found to be significantly aberrant in 15/19 (78.9%) cancers compared with corresponding normal tissues; LEPROT was downregulated in 12 cancers and upregulated in three cancers. LEPROT expressions were overall negatively correlated with its methylation alterations. Moreover, LEPROT was profoundly correlated with the TME, including immune checkpoints, TIIs, and CAFs. According to co-expression analyses and functional enrichments, the interactions of LEPROT with the TME may be mediated by the interleukin six signal transducer/the Janus kinase/signal transducers and activators of the transcription signaling pathway. Prognostic values may exist for LEPROT to predict patient survival and immunotherapy response in a context-dependent way.Conclusions:LEPROT affects cancer development by interfering with the TME and regulating inflammatory or immune signals. LEPROT may also serve as a potential prognostic marker or a target in cancer therapy. This is the first study to investigate the roles of LEPROT across pan-cancer.

show abstract

“… 9 , 10 TRDMT1 methylates tRNA Asp‐GUC , tRNA Gly‐GCC , tRNA Val‐AAC , tRNA Glu‐CUC , tRNA Val‐CAC , and tRNA Gln‐CUG at the C5 position of C38 close to the anticodon. 11 , 12 This tRNA methylation function has been associated with tRNA stability and protein synthesis. 13 TRDMT1 has been implicated in regulation of brain development, myocardial hypertrophy, transgenerational inheritance, hematopoietic stem cell (HSC) steady state, human immunodeficiency virus (HIV) infection, and drug sensitivity.…”

Section: Introductionmentioning

confidence: 99%

TRDMT1 exhibited protective effects against LPS‐induced inflammation in rats through TLR4‐NF‐κB/MAPK‐TNF‐α pathway

Zhang

et al. 2022

Anim Models and Exp Med

View full text Add to dashboard Cite

Background Inflammation is a complex physiological and pathological process. Although many types of inflammation are well characterized, their physiological functions are largely unknown. tRNA aspartic acid methyltransferase 1 (TRDMT1) has been implicated as a stress‐related protein, but its intrinsic biological role is unclear. Methods We constructed a Trdmt1 knockout rat and adopted the LPS‐induced sepsis model. Survival curve, histopathological examination, expression of inflammatory factors, and protein level of TLR4 pathway were analyzed. Results Trdmt1 deletion had no obvious impact on development and growth. Trdmt1 deletion slightly increased the mortality during aging. Our data showed that Trdmt1 strongly responded in LPS‐treated rats, and Trdmt1 knockout rats were vulnerable to LPS treatment with declined survival rate. We also observed more aggravated tissue damage and more cumulative functional cell degeneration in LPS‐treated knockout rats compared with control rats. Further studies showed upregulated TNF‐α level in liver, spleen, lung, and serum tissues, which may be explained by enhanced p65 and p38 phosphorylation. Conclusions Our data demonstrated that Trdmt1 plays a protective role in inflammation by regulating the TLR4‐NF‐κB/MAPK‐TNF‐α pathway. This work provides useful information to understand the TRDMT1 function in inflammation.

show abstract

New substrates and determinants for tRNA recognition of RNA methyltransferase DNMT2/TRDMT1

Cited by 22 publications

References 70 publications

Position 34 of tRNA is a discriminative element for m5C38 modification by human DNMT2

Position 34 of tRNA is a discriminative element for m5C38 modification by human DNMT2

Leptin Receptor Overlapping Transcript (LEPROT) Is Associated with the Tumor Microenvironment and a Prognostic Predictor in Pan-Cancer

TRDMT1 exhibited protective effects against LPS‐induced inflammation in rats through TLR4‐NF‐κB/MAPK‐TNF‐α pathway

Contact Info

Product

Resources

About