METTL4 is an snRNA m6Am methyltransferase that regulates RNA splicing

Chen, Hao; Gu, Lei; Orellana, Esteban A.; Wang, Yuanyuan; Guo, Jiaojiao; Liu, Qi; Wang, Long; Shen, Zhangfei; Wu, Hao; Gregory, Richard I.; Xing, Yi; Shi, Yang

doi:10.1038/s41422-019-0270-4

Cited by 100 publications

(99 citation statements)

References 15 publications

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“…Murine MettL4 was reported to be responsible for N6mA deposition in genic elements, corresponding with transcriptional silencing ( 10 ). Interestingly, recombinant human MettL4 expressed in HEK293T cells has in vitro enzymatic activity on mitochondrial D NA ( 21 ), whereas recombinant human MettL4 expressed in E. coli has R NA MTase activity ( 29 ). The former study showed that MettL4 localizes with mitochondria in all tested tissues ( 21 ) and the latter study found mainly nuclear localization of an exogenously introduced MettL4, and failed to identify appreciable levels of N6mA in mitochondrial DNA ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

“…Murine MettL4 is responsible for N6mA deposition in genic elements associated with transcriptional silencing ( 10 ). Intriguingly, recombinant human MettL4 expressed in human embryonic kidney (HEK293T) cells has in vitro enzymatic activity on mitochondrial D NA ( 21 ), whereas recombinant human MettL4 purified from Escherichia coli has R NA MTase activity ( 29 ).…”

Section: Introductionmentioning

confidence: 99%

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Biochemical and structural basis for YTH domain of human YTHDC1 binding to methylated adenine in DNA

Woodcock

Horton

Zhou

et al. 2020

Nucleic Acids Research

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The recently characterized mammalian writer (methyltransferase) and eraser (demethylase) of the DNA N6-methyladenine (N6mA) methyl mark act on single-stranded (ss) and transiently-unpaired DNA. As YTH domain-containing proteins bind N6mA-containing RNA in mammalian cells, we investigated whether mammalian YTH domains are also methyl mark readers of N6mA DNA. Here, we show that the YTH domain of YTHDC1 (known to localize in the nucleus) binds ssDNA containing N6mA, with a 10 nM dissociation constant. This binding is stronger by a factor of 5 than in an RNA context, tested under the same conditions. However, the YTH domains of YTHDF2 and YTHDF1 (predominantly cytoplasmic) exhibited the opposite effect with ∼1.5–2× stronger binding to ssRNA containing N6mA than to the corresponding DNA. We determined two structures of the YTH domain of YTHDC1 in complex with N6mA-containing ssDNA, which illustrated that YTHDC1 binds the methylated adenine in a single-stranded region flanked by duplexed DNA. We discuss the hypothesis that the writer-reader-eraser of N6mA-containining ssDNA is associated with maintaining genome stability. Structural comparison of YTH and SRA domains (the latter a DNA 5-methylcytosine reader) revealed them to be diverse members of a larger family of DNA/RNA modification readers, apparently having originated from bacterial modification-dependent restriction enzymes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biochemical and structural basis for YTH domain of human YTHDC1 binding to methylated adenine in DNA

Woodcock

Horton

Zhou

et al. 2020

Nucleic Acids Research

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“…is a terminal modification at mRNA cap (usually occurs in the first and sometimes the second nucleotide after the N 7 -methylguanosine (m 7 G) cap) in higher eukaryotic mRNAs and ncRNAs, expecially snRNAs, as well as viral RNAs [109]. m 6 A m plays essential roles in RNA splicing [110], snRNA biogenesis [111], mRNA stability [112] and cap-dependent translation [113]. In human beings, phosphorylated CTD interacting factor 1 (PCIF1, also known as cap-specific adenosine methyltransferase, CAPAM) and methyltransferase-like 4 (METTL4) are the m 6 A m writers, the m 6 A eraser FTO also functions as an m 6 A m eraser, and mRNA-decamping enzyme 2 (DCP2) may be one of the m 6 A m readers [109][110][111]114,115].…”

Section: Rna M 6 a M Modification In Gbmmentioning

confidence: 99%

The Emerging Roles of RNA Modifications in Glioblastoma

Dong

Cui

2020

Cancers

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Glioblastoma (GBM) is a grade IV glioma that is the most malignant brain tumor type. Currently, there are no effective and sufficient therapeutic strategies for its treatment because its pathological mechanism is not fully characterized. With the fast development of the Next Generation Sequencing (NGS) technology, more than 170 kinds of covalent ribonucleic acid (RNA) modifications are found to be extensively present in almost all living organisms and all kinds of RNAs, including ribosomal RNAs (rRNAs), transfer RNAs (tRNAs) and messenger RNAs (mRNAs). RNA modifications are also emerging as important modulators in the regulation of biological processes and pathological progression, and study of the epi-transcriptome has been a new area for researchers to explore their connections with the initiation and progression of cancers. Recently, RNA modifications, especially m6A, and their RNA-modifying proteins (RMPs) such as methyltransferase like 3 (METTL3) and α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5), have also emerged as important epigenetic mechanisms for the aggressiveness and malignancy of GBM, especially the pluripotency of glioma stem-like cells (GSCs). Although the current study is just the tip of an iceberg, these new evidences will provide new insights for possible GBM treatments. In this review, we summarize the recent studies about RNA modifications, such as N6-methyladenosine (m6A), N6,2′O-dimethyladenosine (m6Am), 5-methylcytosine (m5C), N1-methyladenosine (m1A), inosine (I) and pseudouridine (ψ) as well as the corresponding RMPs including the writers, erasers and readers that participate in the tumorigenesis and development of GBM, so as to provide some clues for GBM treatment.

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“…On the other hand, the C. elegans genome does contain genes encoding two other known evolutionarily conserved m6A methyltransferases, METTL16 (mett-10) and METTL4 (C18A3.1). It has recently been reported that in multiple organisms, these two methyltransferases methylate N6 positions of adenines in U6 and U2 snRNAs, respectively [6][7][8][9] . In summary, C. elegans ZCCHC4 and METTL5 are primarily rRNA methyltransferases.…”

Section: Analysis Of M6a Rna Methylation In Caenorhabditis Elegansmentioning

confidence: 99%