Structural insights into molecular mechanism for N6-adenosine methylation by MT-A70 family methyltransferase METTL4

Luo, Qiang; Mo, Jiezhen; Chen, Hao; Hu, Zetao; Wu, Jiabing; Liang, Ziyu; Xie, Wei; Du, Kangxi; Peng, Maolin; Li, Yingping; Li, Tianyang; Zhang, Yangyi; Shi, Xun; Shen, Wen‐Hui; Shi, Yang; Ao, Dong; Wang, Hailin; Ma, Jinbiao

doi:10.1038/s41467-022-33277-x

Cited by 34 publications

(26 citation statements)

References 54 publications

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“…m6A modification is reversibly modulated through the installation of methyl transferases (writers), the removal of a methyl group by demethylases (erasers), and the recognition of m6A binding proteins (readers) [ 22 , 23 ]. m6A writers and associated proteins (m6A writer complex) include Vir-like m6A methyl transferase-associated protein (VIRMA) [ 24 ], methyl transferase-like protein 3 (METTL3) [ 25 ], METTL4 [ 26 ], MTTL5 [ 27 ], METTL14 [ 28 ], METTL 16 [ 29 ], Wilms’ tumor 1 associated protein (WTAP) [ 30 , 31 ], RNA-binding motif protein 15/15B (RBM15/15B) [ 32 ], casitas B-lineage lymphoma-transforming sequence-like protein 1 (CBLL1) [ 33 ], zinc finger CCCH-type containing 13 (ZC3H13), and zinc finger CCHC-type containing 4 (ZCCHC4) [ 5 , 34 , 35 , 36 , 37 , 38 ]. RBM15/15B, VIRMA, CBLL1, ZCCHC4, and ZC3H13 act as associated proteins of m6A writers.…”

Section: Regulators Of Rna Methylationmentioning

confidence: 99%

Roles of RNA Methylations in Cancer Progression, Autophagy, and Anticancer Drug Resistance

Shim

Jeoung

2023

IJMS

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RNA methylations play critical roles in RNA processes, including RNA splicing, nuclear export, nonsense-mediated RNA decay, and translation. Regulators of RNA methylations have been shown to be differentially expressed between tumor tissues/cancer cells and adjacent tissues/normal cells. N6-methyladenosine (m6A) is the most prevalent internal modification of RNAs in eukaryotes. m6A regulators include m6A writers, m6A demethylases, and m6A binding proteins. Since m6A regulators play important roles in regulating the expression of oncogenes and tumor suppressor genes, targeting m6A regulators can be a strategy for developing anticancer drugs. Anticancer drugs targeting m6A regulators are in clinical trials. m6A regulator-targeting drugs could enhance the anticancer effects of current chemotherapy drugs. This review summarizes the roles of m6A regulators in cancer initiation and progression, autophagy, and anticancer drug resistance. The review also discusses the relationship between autophagy and anticancer drug resistance, the effect of high levels of m6A on autophagy and the potential values of m6A regulators as diagnostic markers and anticancer therapeutic targets.

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Section: Regulators Of Rna Methylationmentioning

confidence: 99%

Roles of RNA Methylations in Cancer Progression, Autophagy, and Anticancer Drug Resistance

Shim

Jeoung

2023

IJMS

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“…METTL3, a 70 kDa protein also named MT-A70, was first identified and isolated from mammalian cell nuclear extracts in 1997 [ 6 ]. It belongs to the conserved family of methyltransferases, possessing a methyltransferase domain [MTD] that catalyzes methyl transfer to adenosine [ 6 ]. The N-terminus of METTL3 contains two Cys-Cys-Cys-His (CCCH)-type zinc finger (ZnF) motifs common in RNA-binding proteins [ 7 ].…”

Section: Structure and Function Of Mettl3mentioning

confidence: 99%

The Regulatory Network of METTL3 in the Nervous System: Diagnostic Biomarkers and Therapeutic Targets

2023

Biomolecules

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Methyltransferase-like 3 (METTL3) is a typical component of N6-methyladenosine writers that exhibits methyltransferase activity and deposits methyl groups on RNA. Currently, accumulating studies have demonstrated the involvement of METTL3 in the regulation of neuro-physiological and pathological events. However, no reviews have comprehensively summarized and analyzed the roles and mechanisms of METTL3 in these events. Herein, we are focused on reviewing the roles of METTL3 in regulating normal neurophysiological (Neurogenesis, Synaptic Plasticity and Glial Plasticity, Neurodevelopment, Learning and Memory,) and neuropathological (Autism Spectrum Disorder, Major Depressive Disorder, Neurodegenerative disorders, Brain Tumors, Brain Injuries, and Other Brain Disorders) events. Our review found that although the down-regulated levels of METTL3 function through different roles and mechanisms in the nervous system, it primarily inactivates neuro-physiological events and triggers or worsens neuropathological events. In addition, our review suggests that METTL3 could be used as a diagnostic biomarker and therapeutic target in the nervous system. Collectively, our review has provided an up-to-date research outline of METTL3 in the nervous system. In addition, the regulatory network for METTL3 in the nervous system has been mapped, which could provide directions for future research, biomarkers for clinical diagnosis, and targets for disease treatment. Furthermore, this review has provided a comprehensive view, which could improve our understanding of METTL3 functions in the nervous system.

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“…Instead, FIO1 installs m 6 A into U6 small nuclear (sn)RNA, a small subset of poly(A) + RNA, and several phenotype-related mRNAs, thereby regulating the mRNA stability and many developmental processes [ 62 ]. Another example of independent methyl transferase that is found in Arabidopsis is MTC (an orthologue of METTL4) [ 63 ]. The structural comparison revealed that Arabidopsis MTC homodimer shared similar features with the METTL3-METTL14 heterodimer, suggesting that MTC functions as the m 6 A writer [ 63 ].…”

Section: M 6 a In Plantsmentioning

confidence: 99%

“…Another example of independent methyl transferase that is found in Arabidopsis is MTC (an orthologue of METTL4) [ 63 ]. The structural comparison revealed that Arabidopsis MTC homodimer shared similar features with the METTL3-METTL14 heterodimer, suggesting that MTC functions as the m 6 A writer [ 63 ]. MTC displayed N6 −2′-O-dimethyladenosine (m 6 Am) in vivo and N6 -methylation of 2′-O-methyladenosine (Am) within single-stranded RNA in vitro [ 63 ].…”

Section: M 6 a In Plantsmentioning

confidence: 99%

“…The structural comparison revealed that Arabidopsis MTC homodimer shared similar features with the METTL3-METTL14 heterodimer, suggesting that MTC functions as the m 6 A writer [ 63 ]. MTC displayed N6 −2′-O-dimethyladenosine (m 6 Am) in vivo and N6 -methylation of 2′-O-methyladenosine (Am) within single-stranded RNA in vitro [ 63 ]. However, whether these methyl transferases act independently or cooperatively with other proteins for m 6 A methylation requires further investigation.…”

Section: M 6 a In Plantsmentioning

confidence: 99%

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Current Insights into m6A RNA Methylation and Its Emerging Role in Plant Circadian Clock

Chuong

Doan

Wang

et al. 2023

Plants

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N6-adenosine methylation (m6A) is a prevalent form of RNA modification found in the expressed transcripts of many eukaryotic organisms. Moreover, m6A methylation is a dynamic and reversible process that requires the functioning of various proteins and their complexes that are evolutionarily conserved between species and include methylases, demethylases, and m6A-binding proteins. Over the past decade, the m6A methylation process in plants has been extensively studied and the understanding thereof has drastically increased, although the regulatory function of some components relies on information derived from animal systems. Notably, m6A has been found to be involved in a variety of factors in RNA processing, such as RNA stability, alternative polyadenylation, and miRNA regulation. The circadian clock in plants is a molecular timekeeping system that regulates the daily and rhythmic activity of many cellular and physiological processes in response to environmental changes such as the day-night cycle. The circadian clock regulates the rhythmic expression of genes through post-transcriptional regulation of mRNA. Recently, m6A methylation has emerged as an additional layer of post-transcriptional regulation that is necessary for the proper functioning of the plant circadian clock. In this review, we have compiled and summarized recent insights into the molecular mechanisms behind m6A modification and its various roles in the regulation of RNA. We discuss the potential role of m6A modification in regulating the plant circadian clock and outline potential future directions for the study of mRNA methylation in plants. A deeper understanding of the mechanism of m6A RNA regulation and its role in plant circadian clocks will contribute to a greater understanding of the plant circadian clock.

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Structural insights into molecular mechanism for N6-adenosine methylation by MT-A70 family methyltransferase METTL4

Cited by 34 publications

References 54 publications

Roles of RNA Methylations in Cancer Progression, Autophagy, and Anticancer Drug Resistance

Roles of RNA Methylations in Cancer Progression, Autophagy, and Anticancer Drug Resistance

The Regulatory Network of METTL3 in the Nervous System: Diagnostic Biomarkers and Therapeutic Targets

Current Insights into m6A RNA Methylation and Its Emerging Role in Plant Circadian Clock

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