tRNA deamination by ADAT requires substrate-specific recognition mechanisms and can be inhibited by tRFs

Frigolé, Helena Roura; Camacho, Noelia; Coma, Maria Castellví; Fernández-Lozano, Carla; García-Lema, Jorge; Rafels-Ybern, Àlbert; Canals, Albert; Coll, Miquel; Pouplana, Lluı́s Ribas de

doi:10.1261/rna.068189.118

Cited by 14 publications

(9 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the capacity of movement of ADAT3-N should be essential to facilitate the binding of the tRNAs and the strict positioning of their anticodon loop into the ADAT2 active site. Thus, the differences that we and others ( 24 ) observe in the recognition and the processing of cognate tRNAs by ADAT could be explained by different binding of those tRNAs to the ADAT active site but also onto ADAT3-N.…”

Section: Discussionmentioning

confidence: 49%

“…This is in agreement with the apparent loss of some recognition determinants observed in the ADAT2 anticodon loop bases recognition pockets. In turn, this has constrained the ADAT complex to change to recognize specifically tRNA macromolecules, in agreement with the fact that the full tRNA tertiary structure, and not only the ASL, is required for ADAT activity ( 14 , 23 , 24 ).…”

Section: Discussionmentioning

confidence: 66%

“…Interestingly, our deamination experiments show that ADAT does not process equally its various cognate tRNAs. Notably, tRNA Ala (AGC) appears less sensitive to ADAT perturbations, especially those affecting mildly ADAT3 N-terminal domain, and differences in the binding of tRNA Arg (ACG) and tRNA Ala (AGC) by ADAT have already been reported ( 24 ). In line with this, tRNA Ala (AGC) interaction with ADAT shows a slightly higher K d around 8 μM.…”

Section: Discussionmentioning

confidence: 98%

“…Additionally, in contrast to TadA, the ADAT heterodimeric complex requires a full tRNA to perform its deamination reaction. Specifically, both the tRNA tertiary structure and the tRNA strict positioning are essential for ADAT activity ( 14 , 23 , 24 ).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The structure of the mouse ADAT2/ADAT3 complex reveals the molecular basis for mammalian tRNA wobble adenosine-to-inosine deamination

Ramos‐Morales

Bayam

Del-Pozo-Rodríguez

et al. 2021

Nucleic Acids Research

View full text Add to dashboard Cite

Post-transcriptional modification of tRNA wobble adenosine into inosine is crucial for decoding multiple mRNA codons by a single tRNA. The eukaryotic wobble adenosine-to-inosine modification is catalysed by the ADAT (ADAT2/ADAT3) complex that modifies up to eight tRNAs, requiring a full tRNA for activity. Yet, ADAT catalytic mechanism and its implication in neurodevelopmental disorders remain poorly understood. Here, we have characterized mouse ADAT and provide the molecular basis for tRNAs deamination by ADAT2 as well as ADAT3 inactivation by loss of catalytic and tRNA-binding determinants. We show that tRNA binding and deamination can vary depending on the cognate tRNA but absolutely rely on the eukaryote-specific ADAT3 N-terminal domain. This domain can rotate with respect to the ADAT catalytic domain to present and position the tRNA anticodon-stem-loop correctly in ADAT2 active site. A founder mutation in the ADAT3 N-terminal domain, which causes intellectual disability, does not affect tRNA binding despite the structural changes it induces but most likely hinders optimal presentation of the tRNA anticodon-stem-loop to ADAT2.

show abstract

Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The structure of the mouse ADAT2/ADAT3 complex reveals the molecular basis for mammalian tRNA wobble adenosine-to-inosine deamination

Ramos‐Morales

Bayam

Del-Pozo-Rodríguez

et al. 2021

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

“…Our present study screened the MAPK signaling pathway by bioinformatic analysis, and this was further confirmed by immunoblotting. Analogously, some other pathways, related to tsRNAs, had also been reported by a few studies (25,26). With regard to the MAPK signaling pathway, it has been uncovered and widely accepted as a pathway that could promote the progression of tumors (27)(28)(29)(30)(31).…”

Section: Discussionmentioning

confidence: 81%

tRNA-Derived Fragment tRF-Glu-TTC-027 Regulates the Progression of Gastric Carcinoma via MAPK Signaling Pathway

Zhou

Wang

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

Transfer RNA-derived RNA fragments (tRFs) belong to non-coding RNAs (ncRNAs) discovered in most carcinomas. Although some articles have demonstrated the characteristics of tRFs in gastric carcinoma (GC), the underlying mechanisms still need to be elucidated. Meanwhile, it was reported that the MAPK pathway was momentous in GC progression. Thus we focused on investigating whether tRF-Glu-TTC-027 could act as a key role in the progression of GC with the regulation of the MAPK pathway. We collected the data of the tRNA-derived fragments expression profile from six paired clinical GC tissues and corresponding adjacent normal samples in this study. Then we screened tRF-Glu-TTC-027 for analysis by using RT-PCR. We transfected GC cell lines with tRF-Glu-TTC-027 mimics or mimics control. Then the proliferation, migration, and invasion assays were performed to assess the influence of tRF-Glu-TTC-027 on GC cell lines. Fluorescence in situ hybridization assay was conducted to confirm the cell distribution of tRF-Glu-TTC-027. We confirmed the mechanism that tRF-Glu-TTC-027 influenced the MAPK signaling pathway and observed a strong downregulation of tRF-Glu-TTC-027 in clinical GC samples. Overexpression of tRF-Glu-TTC-027 suppressed the malignant activities of GC in vitro and in vivo. MAPK signaling pathway was confirmed to be a target pathway of tRF-Glu-TTC-027 in GC by western blot. This is the first study to show that tRF-Glu-TTC-027 was a new tumor-suppressor and could be a potential object for molecular targeted therapy in GC.

show abstract

Impact of Chemical Modification ontRNAFunction

Howell¹,

Jackman²

2019

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Post‐transcriptional tRNA modifications play a critical role in ensuring a high‐quality pool of tRNA for participation in cellular translation. Despite their importance, important questions remain about the impacts of individual tRNA modifications on tRNA structure and function. Similarly, biological consequences of the absence of tRNA modifications have begun to be characterised in detail only recently. tRNA modifications have important impacts on biology, ranging from important impacts on individual tRNA molecules, to powerful effects on cellular function, and finally important roles in human health and disease. Key Concepts tRNA modifications occur at high frequency and with great chemical diversity. tRNA modifications fine‐tune tRNA structure and function. Through their effects on individual tRNA molecules, the impacts of tRNA modifications propagate to the cellular and organismal levels. tRNA modifications can regulate translation and impact protein homeostasis. Lack of tRNA modifications has been implicated in human diseases, such as neurological disorders, glucose metabolic defects and cancer.

show abstract

tRNA deamination by ADAT requires substrate-specific recognition mechanisms and can be inhibited by tRFs

Cited by 14 publications

References 61 publications

The structure of the mouse ADAT2/ADAT3 complex reveals the molecular basis for mammalian tRNA wobble adenosine-to-inosine deamination

The structure of the mouse ADAT2/ADAT3 complex reveals the molecular basis for mammalian tRNA wobble adenosine-to-inosine deamination

tRNA-Derived Fragment tRF-Glu-TTC-027 Regulates the Progression of Gastric Carcinoma via MAPK Signaling Pathway

Impact of Chemical Modification ontRNAFunction

Contact Info

Product

Resources

About