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Structures and mechanisms of tRNA methylation by METTL1-WDR4.

ABSTRACT: Specific, regulated modification of RNAs is important for proper gene expression^1,2. tRNAs are rich with various chemical modifications that affect their stability and function^3,4. 7-Methylguanosine (m⁷G) at tRNA position 46 is a conserved modification that modulates steady-state tRNA levels to affect cell growth^5,6. The METTL1-WDR4 complex generates m⁷G46 in humans, and dysregulation of METTL1-WDR4 has been linked to brain malformation and multiple cancers^7-22. Here we show how METTL1 and WDR4 cooperate to recognize RNA substrates and catalyse methylation. A crystal structure of METTL1-WDR4 and cryo-electron microscopy structures of METTL1-WDR4-tRNA show that the composite protein surface recognizes the tRNA elbow through shape complementarity. The cryo-electron microscopy structures of METTL1-WDR4-tRNA with S-adenosylmethionine or S-adenosylhomocysteine along with METTL1 crystal structures provide additional insights into the catalytic mechanism by revealing the active site in multiple states. The METTL1 N terminus couples cofactor binding with conformational changes in the tRNA, the catalytic loop and the WDR4 C terminus, acting as the switch to activate m⁷G methylation. Thus, our structural models explain how post-translational modifications of the METTL1 N terminus can regulate methylation. Together, our work elucidates the core and regulatory mechanisms underlying m⁷G modification by METTL1, providing the framework to understand its contribution to biology and disease.

SUBMITTER: Ruiz-Arroyo VM

PROVIDER: S-EPMC9930641 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Structures and mechanisms of tRNA methylation by METTL1-WDR4.

Ruiz-Arroyo Victor M VM Raj Rishi R Babu Kesavan K Onolbaatar Otgonbileg O Roberts Paul H PH Nam Yunsun Y

Nature 20230104 7943

Specific, regulated modification of RNAs is important for proper gene expression1,2. tRNAs are rich with various chemical modifications that affect their stability and function3,4. 7-Methylguanosine (m7G) at tRNA position 46 is a conserved modification that modulates steady-state tRNA levels to affect cell growth5,6. The METTL1-WDR4 complex generates m7G46 in humans, and dysregulation of METTL1-WDR4 has been linked to brain malformation and ...[more]

PMID: 36599982

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Project description:BackgroundCancer cells selectively promote the translation of oncogenic transcripts to stimulate cancer progression. Although growing evidence has revealed that tRNA modifications and related genes participate in this process, their roles in head and neck squamous cell carcinoma (HNSCC) remain largely uncharacterized. Here, we sought to investigate the function and mechanisms of the transfer RNA (tRNA) N7-methylguanosine (m7 G) modification in regulating the occurrence and development of HNSCC.MethodsCell lost-of-function and gain-of-function assays, xenograft models, conditional knockout and knockin mouse models were used to study the physiological functions of tRNA m7 G modification in HNSCC tumorigenesis. tRNA modification and expression profiling, mRNA translation profiling and rescue assays were performed to uncover the underlying molecular mechanisms. Single-cell RNA sequencing (scRNA-seq) was conducted to explore the tumor microenvironment changes.ResultsThe tRNA m7 G methyltransferase complex components Methyltransferase-like 1 (METTL1)/WD repeat domain 4 (WDR4) were upregulated in HNSCC and associated with a poor prognosis. Functionally, METTL1/WDR4 promoted HNSCC progression and metastasis in cell-based and transgenic mouse models. Mechanistically, ablation of METTL1 reduced the m7 G levels of 16 tRNAs, inhibiting the translation of a subset of oncogenic transcripts, including genes related to the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. In addition, chemical modulators of the PI3K/Akt/mTOR signaling pathway reversed the effects of Mettl1 in mouse HNSCC. Furthermore, scRNA-seq results revealed that Mettl1 knockout in mouse tumor cells altered the immune landscape and cell-cell interaction between the tumor and stromal compartment.ConclusionsThe tRNA m7 G methyltransferase METTL1 was found to promote the development and malignancy of HNSCC through regulating global mRNA translation, including the PI3K/AKT/mTOR signaling pathway, and found to alter immune landscape. METTL1 could be a promising treatment target for HNSCC patients.

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Structures and mechanisms of tRNA methylation by METTL1-WDR4.

Publications

Structures and mechanisms of tRNA methylation by METTL1-WDR4.

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