☆ 4.6 Review

Interconnections between m6A RNA modification, RNA structure, and protein-RNA complex assembly

LIFE SCIENCE ALLIANCE (2023)

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Article Biochemistry & Molecular Biology

Exclusion of m6A from splice-site proximal regions by the exon junction complex dictates m6A topologies and mRNA stability

Anna Uzonyi et al.

Summary: N6-methyladenosine (m6A) is a widespread destabilizing mark on mRNA with non-uniform distribution across the transcriptome. In this study, the authors propose that m6A deposition is exclusion-based rather than selective. They demonstrate that m6A consensus motifs are methylated by default unless they are near splice junctions. By validating a simple model based on the presence of m6A motifs and exon-intron architecture, they show that mRNA decay is mechanistically mediated via m6A.

MOLECULAR CELL (2023)

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Review Biochemistry & Molecular Biology

RNA m6A methylation across the transcriptome

Erdem Sendinc et al.

Summary: Since the discovery of chemical modifications on RNA and DNA, N6-methyl adenosine (m6A) has been found to be highly abundant in mammalian cells, not only on protein-coding transcripts but also on non-coding RNAs, mediated by evolutionarily conserved enzymes. Recent research has shed light on the nuclear roles of m6A in regulating chromatin states and gene expression, as well as the discovery of evolutionarily conserved methyltransferases that catalyze methylation on various RNAs. Further research is needed to understand the molecular mechanisms and functions of m6A in health and disease, considering its involvement in important biological processes.

MOLECULAR CELL (2023)

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Article Multidisciplinary Sciences

Exon architecture controls mRNA m6A suppression and gene expression

P. Cody He et al.

Summary: N-6-methyladenosine (m6A) is the most prevalent modification in messenger RNA (mRNA) and plays important roles in various physiological processes. The specificity of m(6)A is globally regulated by suppressors, such as exon junction complexes (EJCs), which protect exon junction-proximal RNA and inhibit m6A deposition. The suppression of m6A by EJCs is a key determinant of mRNA m(6)A specificity and is influenced by exon architecture.

SCIENCE (2023)

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Review Genetics & Heredity

Genetic and epigenetic defects of the RNA modification machinery in cancer

Ines Orsolic et al.

Summary: Cancer was once believed to be solely genetic, but now it is known that dysregulated genetic and epigenetic mechanisms work together in cancer development. Recently, the epitranscriptome, which refers to chemical modifications of RNA molecules, has been found to play a role in regulating RNA function. Specific enzymes responsible for these modifications, known as RMPs, are being investigated for their potential as therapeutic targets or diagnostic markers in cancer. The study of epitranscriptomics has revealed the critical role of RNA modifications in cellular pathways and their potential importance in cancer treatment.

TRENDS IN GENETICS (2023)

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Article Multidisciplinary Sciences

The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators

Lisa-Marie Appel et al.

Summary: The heptad repeats of the C-terminal domain (CTD) of RNA polymerase II (Pol II) are extensively modified throughout the transcription cycle. The SPOC domain was identified as a CTD reader domain specifically binding to phosphorylated serine residues. The SPOC domains of DIDO, SHARP, and RBM15 can act as CTD readers and also recognize other phosphorylated binding partners.

NATURE COMMUNICATIONS (2023)

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Review Biochemistry & Molecular Biology

mRNA Regulation by RNA Modifications

Wendy V. Gilbert et al.

Summary: Chemical modifications on mRNA play a crucial role in gene expression regulation, and research in this area has been rapidly advancing in the past decade. mRNA modifications have been found to influence various stages of mRNA life cycle, but the underlying molecular mechanisms are still not fully understood. This article summarizes recent studies that have shed light on the roles of mRNA modifications, identifies knowledge gaps and unanswered questions, and provides insights for future research directions in this field.

ANNUAL REVIEW OF BIOCHEMISTRY (2023)

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Review Genetics & Heredity

Biological roles of adenine methylation in RNA

Konstantinos Boulias et al.

Summary: Boulias and Greer review the functions of N-6-methyladenosine (m(6)A) in RNA, covering its impact on RNA substrates, chromatin architecture, gene expression regulation, genome stability, as well as its roles in stem-cell differentiation, neurogenesis, and immunity.

NATURE REVIEWS GENETICS (2023)

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Article Biochemistry & Molecular Biology

RBM33 is a unique m6A RNA-binding protein that regulates ALKBH5 demethylase activity and substrate selectivity

Fang Yu et al.

Summary: In this study, RBM33 was identified as a previously unrecognized m6A-binding protein that forms a complex with ALKBH5, thereby activating its demethylase activity. RBM33 plays a critical role in the tumorigenesis of head-neck squamous cell carcinoma by recruiting ALKBH5 to demethylate and stabilize DDIT4 mRNA, promoting autophagy.

MOLECULAR CELL (2023)

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Article Pharmacology & Pharmacy

The structure and function of YTHDF epitranscriptomic m6A readers

Vilbert Sikorski et al.

TRENDS IN PHARMACOLOGICAL SCIENCES (2023)

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Article Multidisciplinary Sciences

The m6A reader PRRC2A is essential for meiosis I completion during spermatogenesis

Xinshui Tan et al.

Summary: The m6A reader PRRC2A plays a critical role in male fertility and meiotic cell cycle. It regulates RNA abundance and translation efficiency of target transcripts, especially spermatogonia-specific ones. PRRC2A also interacts with proteins involved in mRNA metabolism and translation.

NATURE COMMUNICATIONS (2023)

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Article Cell Biology

METTL14 is a chromatin regulator independent of its RNA N-6-methyladenosine methyltransferase activity

Xiaoyang Dou et al.

Summary: METTL3 and METTL14, as core components of the main RNA m(6)A methyltransferase complex, play distinct roles in stemness maintenance and differentiation of mESCs. While depletion of METTL3 leads to transcription upregulation, depletion of METTL14 results in global gene suppression. Moreover, METTL14 is involved in the regulation of H3K27me3 independent of METTL3, which critically impacts transcriptional regulation and differentiation of mESCs.

PROTEIN & CELL (2023)

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Article Multidisciplinary Sciences

7SK methylation by METTL3 promotes transcriptional activity

Marcelo Perez-Pepe et al.

Summary: A fundamental feature of cell signaling is the conversion of extracellular signals into adaptive transcriptional responses. The role of RNA modifications in this process is poorly understood. We found that epidermal growth factor signaling induces phosphorylation of the enzyme methyltransferase 3 (METTL3), leading to METTL3-mediated methylation of 7SK. 7SK methylation enhances its binding to heterogeneous nuclear ribonucleoproteins, causing the release of the HEXIM1/P-TEFb complex and inducing transcriptional elongation. Our findings establish the mechanism underlying 7SK activation and uncover a previously unknown function for the m6A modification in converting growth factor signaling events into a regulatory transcriptional response via an RNA methylation-dependent switch.

SCIENCE ADVANCES (2023)

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Review Biochemistry & Molecular Biology

Emerging Quantitative Biochemical, Structural, and Biophysical Methods for Studying Ribosome and Protein-RNA Complex Assembly

Kavan Gor et al.

Summary: Ribosome assembly is a crucial process in gene expression, and studying its molecular mechanisms has led to the development of novel approaches for investigating the assembly of other RNA-protein complexes. This review discusses biochemical, structural, and biophysical methods that have been used to understand the complex process of bacterial ribosome assembly. It also explores emerging approaches for studying how transcription, RNA processing, cellular factors, and the cellular environment influence ribosome and RNA-protein complex assembly.

BIOMOLECULES (2023)

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Article Biochemistry & Molecular Biology

METTL3 protects METTL14 from STUB1-mediated degradation to maintain m6A homeostasis

Zhan-Cheng Zeng et al.

Summary: METTL14 stability is regulated by competition between METTL3 and E3 ligase STUB1. STUB1 interacts with METTL14 and mediates its ubiquitination and subsequent degradation, leading to decreased m(6)A levels. Amino acid regions 450-454 and 464-480 of METTL3 are essential for promoting METTL14 stabilization. Modulating STUB1 expression affects METTL14 protein levels, m(6)A modification, and tumorigenesis. These findings uncover an ubiquitination mechanism controlling METTL14 protein levels to fine-tune m(6)A homeostasis. Modulating STUB1 expression to degrade METTL14 could represent a promising therapeutic strategy against cancer.

EMBO REPORTS (2023)

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Article Biochemistry & Molecular Biology

N6-methyladenosine in 7SK small nuclear RNA underlies RNA polymerase II transcription regulation

Yuzhi Wang et al.

Summary: This study reveals that N6-methyladenosine modifications on a non-coding RNA, 7SK, play a crucial role in regulating RNA polymerase II transcription in non-small cell lung cancer. The removal of this modification leads to structural rearrangements in 7SK, resulting in the sequestration of positive transcription elongation factor b (P-TEFb) complex and a reduction in RNA polymerase II activity. This finding sheds light on the mechanism of how m6A modifications regulate tumorigenesis in NSCLC.

MOLECULAR CELL (2023)

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Article Biochemistry & Molecular Biology

Direct m6A recognition by IMP1 underlays an alternative model of target selection for non-canonical methyl-readers

Giuseppe Nicastro et al.

Summary: m6A methylation is an important regulatory layer in organismal development and is associated with various cancers and neuro-pathologies. RNA binding proteins, known as m6A readers, integrate the information encoded by m6A methylation into existing RNA regulatory networks. This study reveals that the reader IMP1 recognizes m6A through a specific hydrophobic platform, forming a stable and high-affinity interaction. The recognition is conserved across evolution and independent of the sequence context, but builds upon the strong sequence specificity of IMP1 for GGAC RNA. These findings propose a context-dependent role for methylation in the recognition of IMP1 targets, dependent on the cellular concentration of IMP1, as opposed to the YTH proteins.

NUCLEIC ACIDS RESEARCH (2023)

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Article Multidisciplinary Sciences

Modulation of translational decoding by m(6)A modification of mRNA

Sakshi Jain et al.

Summary: m(6)A is a common mRNA modification that regulates cellular mRNA metabolism. It delays the decoding process and increases tRNA drop-off from the ribosome by favoring alternative codon conformations that are rejected by the ribosome.

NATURE COMMUNICATIONS (2023)

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Letter Cell Biology

WTAP-VIRMA counteracts dsDNA binding of the m6A writer METTL3-METTL14 complex and maintains N6-adenosine methylation activity

Xuhui Yan et al.

CELL DISCOVERY (2023)

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Article Biochemistry & Molecular Biology

The METTL5-TRMT112 N6-methyladenosine methyltransferase complex regulates mRNA translation via 18S rRNA methylation

Caraline Sepich-Poore et al.

Summary: Ribosomal RNAs (rRNAs) carry various chemical modifications, including m6A, which play important roles in mRNA decoding. We identified the METTL5-TRMT112 methyltransferase complex as responsible for the m6A modification on human 18S rRNA. Loss of METTL5 disrupts gene expression and causes developmental defects in humans and mice.

JOURNAL OF BIOLOGICAL CHEMISTRY (2022)

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Article Biochemistry & Molecular Biology

Structural effects of m(6)A modification of the Xist A-repeat AUCG tetraloop and its recognition by YTHDC1

Alisha N. Jones et al.

Summary: The study reveals the impact of m(6)A modification on the structure and function of lncRNA Xist. The m(6)A modification affects the conformation of AUCG tetraloop hairpin and can be recognized by YTHDC1 reader protein.

NUCLEIC ACIDS RESEARCH (2022)

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Article Biochemistry & Molecular Biology

MODOMICS: a database of RNA modification pathways. 2021 update

Pietro Boccaletto et al.

Summary: MODOMICS database, established since 2006, has evolved from containing basic chemical structures of modified ribonucleosides to a comprehensive resource with new functionalities such as a catalog of RNA modifications linked to human diseases. The database, which is extensively linked to RCSB Protein Data Bank, provides users with an enhanced tool for research on RNA modification.

NUCLEIC ACIDS RESEARCH (2022)

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Article Biochemistry & Molecular Biology

Recognition of G-quadruplex RNA by a crucial RNA methyltransferase component, METTL14

Atsuhiro Yoshida et al.

Summary: The study revealed that the METTL3/METTL14 methyltransferase heterodimer prefers to bind to RNA G-quadruplex structures and selectively methylates adenosines close to these sequences. This finding sheds light on the role of G-quadruplex structures in epitranscriptomic regulation and suggests a possible mechanism for recruitment of the METTL3/METTL14 complex to specific methylation sites.

NUCLEIC ACIDS RESEARCH (2022)

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Review Biochemistry & Molecular Biology

The multifaceted functions of the Fat mass and Obesity-associated protein (FTO) in normal and cancer cells

Sebastien Relier et al.

Summary: Over the past decade, mRNA modification has emerged as a new layer of gene expression regulation. FTO, as the first identified eraser of N6-methyladenosine (m6A) adducts, has attracted much attention in the field of epitranscriptomics. The contradictory studies on the regulatory role of FTO in gene expression may be attributed to its wide spectrum of substrates and RNA sequence preferences. This review focuses on current knowledge related to FTO function in healthy and cancer cells, emphasizing its divergent roles in different tissues and subcellular and molecular contexts.

RNA BIOLOGY (2022)

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Review Genetics & Heredity

The multifaceted effects of YTHDC1-mediated nuclear m6A recognition

Jocelyn Widagdo et al.

Summary: N6-methyladenosine modification is a crucial regulator of gene expression and protein translation. The fate of m6A-modified mRNAs is decoded by m6A readers, with YTHDC1 being the only reader located in the nucleus. In addition to its well-established role in the cytoplasm, recent studies have revealed the involvement of YTHDC1 in regulating noncoding and regulatory RNAs in the nucleus, possibly through the formation of nuclear condensates.

TRENDS IN GENETICS (2022)

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Article Biochemistry & Molecular Biology

Dynamic assembly of the mRNA m6A methyltransferase complex is regulated by METTL3 phase separation

Dasol Han et al.

Summary: m(6)A methylation, as a reversible chemical modification on mRNA, plays a crucial role in gene regulation. This study reveals that the recruitment of the mRNA m(6)A methyltransferase writer complex to nuclear speckles is important for its regulation, and its phase state is determined by the binding of the small molecule cofactor SAM.

PLOS BIOLOGY (2022)

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Article Cell Biology

RNA nucleotide methylation: 2021 update

Yuri Motorin et al.

Summary: RNA methylation has re-emerged as an important mechanism in gene regulation, leading to new insights in RNA research; the presence of methyltransferases in disease models and clinical investigations has significantly contributed to the field's progress; the concept of reversibility and dynamics in RNA modification has replaced the previous perception of irreversible RNA maturation, potentially resulting in diverse populations of RNA variants.

WILEY INTERDISCIPLINARY REVIEWS-RNA (2022)

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Article Biology

RNA binding to human METTL3-METTL14 restricts N6-deoxyadenosine methylation of DNA in vitro

Shan Qi et al.

Summary: The METTL3-METTL14 complex catalyzes methylation of RNA and DNA, with a preference for single-stranded DNA and structured RNA, respectively. The complex has a higher affinity for structured RNA but methylates RNA less efficiently than DNA. Furthermore, the methylation of DNA by the complex is restricted by structured RNA elements prevalent in cellular RNAs.

ELIFE (2022)

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Article Biochemistry & Molecular Biology

Dynamic control of chromatin-associated m6A methylation regulates nascent RNA synthesis

Wenqi Xu et al.

Summary: The METTL3/METTL14/WTAP m(6)A methyltransferase complex is responsible for depositing m(6)A modification on nascent transcripts from promoters and enhancers, protecting them from premature termination by the Integrator complex and promoting productive transcription.

MOLECULAR CELL (2022)

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Article Biochemical Research Methods

ColabFold: making protein folding accessible to all

Milot Mirdita et al.

Summary: ColabFold combines fast homology search and optimized model utilization to offer accelerated prediction of protein structures and complexes, with a processing speed that is 40-60 times faster. It serves as a free and accessible platform for protein folding, capable of predicting close to 1,000 structures per day.

NATURE METHODS (2022)

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Article Biochemistry & Molecular Biology

Mechanisms of substrate recognition and N-6-methyladenosine demethylation revealed by crystal structures of ALKBH5-RNA complexes

Simranjeet Kaur et al.

Summary: ALKBH5 is an enzyme responsible for demethylating RNA and has emerged as a potential target for cancer treatment. This study provides insight into the substrate recognition and demethylation mechanism of ALKBH5, and reveals its preference for specific sequences.

NUCLEIC ACIDS RESEARCH (2022)

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Article Biochemistry & Molecular Biology

Specific recognition between YTHDF3 and m6A-modified RNA: An all-atom molecular dynamics simulation study

Wenxue Zhou et al.

Summary: In this study, molecular dynamics simulations were performed to investigate the negative selectivity of YTHDF3 towards unmethylated substrate, shedding light on the mechanism by which YTHDF3 specifically recognizes m(6)A-modified RNA. The results revealed the conformation selectivity and induced-fit in YTHDF3 binding with m(6)A-modified RNA, highlighting the crucial roles of the recognition loop and loop6. The methylation of m(6)A enhanced the stability of the YTHDF3-RNA complex and promoted specific recognition through the anchoring of the methyl group by Trp492 and pi-pi stacking interactions with Trp438 and Trp497.

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS (2022)

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Review Cell Biology

RNA methyltransferase METTL16: Targets and function

Emily R. Satterwhite et al.

Summary: METTL16 is an emerging player in the RNA modification landscape, with multiple RNA interactors and a key role in regulating gene expression through methylation. Its mechanisms and biological functions in the cell are still being explored.

WILEY INTERDISCIPLINARY REVIEWS-RNA (2022)

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Review Biochemistry & Molecular Biology

Epitranscriptome: Review of Top 25 Most-Studied RNA Modifications

Viktoriia A. Arzumanian et al.

Summary: The building blocks for RNA molecules have a larger diversity than the standard four nucleotides due to post-transcriptional biochemical modifications. These modifications, both essential for RNA functions and functioning as dynamic markings, form the epitranscriptome. Over 300 distinct RNA modifications from all three life domains have been identified, but most reviews only cover a few well-established modifications. This study provides a comprehensive overview of the current research status on the epitranscriptome, analyzing the available information for all known RNA modifications and describing the current status of research on most RNA modifications.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

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Article Biology

m6A modification of U6 snRNA modulates usage of two major classes of pre-mRNA 5' splice site

Matthew T. Parker et al.

Summary: Alternative splicing is associated with the evolution of complex eukaryotes. The m(6)A modification of U6 snRNA plays a crucial role in splicing accuracy and efficiency. The sequence composition of splice sites and the cooperative roles of U5 and U6 snRNA are important in splice site selection. U6 snRNA m(6)A modification influences the usage of 3' splice sites. Two major classes of 5' splice site were identified in diverse eukaryotes.

ELIFE (2022)

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Article Multidisciplinary Sciences

Limited effects of m6A modification on mRNA partitioning into stress granules

Anthony Khong et al.

Summary: m(6)A modification has a limited effect on mRNA entry into stress granules.

NATURE COMMUNICATIONS (2022)

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Article Biochemistry & Molecular Biology

Nuclear m6A reader YTHDC1 suppresses proximal alternative polyadenylation sites by interfering with the 3′ processing machinery

Liutao Chen et al.

Summary: The N6-methyladenosine (m(6)A) modification and alternative polyadenylation (APA) are important regulators of gene expression. YTHDC1, an m(6)A reader, was found to suppress proximal APA sites and produce longer 3' UTR transcripts by binding to upstream m(6)A sites. The interaction between YTHDC1 and FIP1L1, as well as the liquid-liquid phase separation promoted by m(6)A binding, may play a crucial role in APA regulation.

EMBO REPORTS (2022)

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Article Virology

WTAP Targets the METTL3 m6A-Methyltransferase Complex to Cytoplasmic Hepatitis C Virus RNA to Regulate Infection

Matthew T. Sacco et al.

Summary: This study reveals that WTAP plays a critical role in the m(6)A modification of HCV RNA by METTL3 and METTL14 in the cytoplasm. The cytoplasmic localization of WTAP is associated with HCV infection, HCV RNA m(6)A modification, and the production of viral particles.

JOURNAL OF VIROLOGY (2022)

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Article Genetics & Heredity

RNA m6A regulates transcription via DNA demethylation and chromatin accessibility

Shuang Deng et al.

Summary: This study reveals that METTL3-mediated RNA N-6-methyladenosine (m(6)A) deposition leads to DNA demethylation. The m(6)A reader protein FXR1 recruits DNA 5-methylcytosine dioxygenase TET1 to chromatin, which is linked to chromatin accessibility and gene transcription.

NATURE GENETICS (2022)

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Article Biochemistry & Molecular Biology

Elucidating the Kinetic Mechanism of Human METTL16

Kurtis Breger et al.

Summary: Methyltransferase-like protein 16 (METTL16) is one of the four catalytically active m6A RNA methyltransferases in humans. This study investigated the kinetic mechanism and biochemical properties of METTL16. The results showed that METTL16 binds to U6 snRNA and the MALAT1 triple helix with high affinity, and the binding occurs in an ordered-sequential mechanism. The findings provide insights into the catalytic activity of METTL16 in biological functions.

BIOCHEMISTRY (2022)

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Review Biochemistry & Molecular Biology

Biological roles of the RNA m6A modification and its implications in cancer

Juyeong Hong et al.

Summary: This study reviews the function of m(6)A modification in cancer and its association with DNA damage response and genomic stability, proposing potential therapeutic strategies.

EXPERIMENTAL AND MOLECULAR MEDICINE (2022)

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Article Cell Biology

Cryo-EM structures of human m6A writer complexes

Shichen Su et al.

Summary: This study reveals the structure and function of the m(6)A writer complex. Cryo-EM and other experimental methods were used to uncover the structure of MACOM and its interaction with MAC.

CELL RESEARCH (2022)

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Article Biochemistry & Molecular Biology

RNA secondary structure dependence in METTL3-METTL14 mRNA methylation is modulated by the N-terminal domain of METTL3

Nathalie Meiser et al.

Summary: The study reveals that N-6-methyladenosine modification is the most abundant in mRNA, with the METTL3-METTL14 complex responsible for catalyzing this modification, which is dependent not only on sequence but also on the secondary structure of RNA. The zinc finger domains within the complex play a crucial role in RNA binding and methylation activity, while the N-terminal domain of METTL3 affects the dependence of methylation yield on secondary structure.

BIOLOGICAL CHEMISTRY (2021)

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Article Biochemistry & Molecular Biology

UCSF ChimeraX: Structure visualization for researchers, educators, and developers

Eric F. Pettersen et al.

Summary: UCSF ChimeraX is a powerful visualization program with enhanced performance and graphics, offering new tools and analysis features, support for various areas like virtual reality, and improved ease of use, along with an app store for researchers to contribute new tools.

PROTEIN SCIENCE (2021)

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Article Biochemistry & Molecular Biology

Enzymatic characterization of three human RNA adenosine methyltransferases reveals diverse substrate affinities and reaction optima

Dan Yu et al.

Summary: The study reveals significant differences in catalytic efficiency and substrate binding affinities among different human RNA methyltransferases, as well as their preferences for pH and ionic strength. It highlights the diversity of enzymatic mechanisms and substrate specificities of RNA adenosine methyltransferases, underscoring the importance of assay optimization in their study.

JOURNAL OF BIOLOGICAL CHEMISTRY (2021)

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Article Biochemistry & Molecular Biology

TonEBP recognizes R-loops and initiates m6A RNA methylation for R-loop resolution

Hyun Je Kang et al.

Summary: R-loops are three-stranded RNA-DNA structures that can cause genomic instability and malignant diseases when accumulated. TonEBP can recognize and bind to R-loops, recruiting METTL3 for m6A RNA methylation, providing a new pathway for R-loop resolution.

NUCLEIC ACIDS RESEARCH (2021)

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Article Biochemistry & Molecular Biology

The comprehensive interactomes of human adenosine RNA methyltransferases and demethylases reveal distinct functional and regulatory features

Helena Covelo-Molares et al.

Summary: N6-methyladenosine (m(6)A) and N6,2 '-O-dimethyladenosine (m(6)Am) are common modifications found in mRNAs and ncRNAs that regulate RNA biology by interacting with specific RNA-binding proteins. These modifications are linked to development, disease, and stress response, and are involved in specific molecular mechanisms with other RNA modifiers and processing factors. The identified methyltransferases and demethylases have limited spatial interactomes, pointing to their regulation through specific molecular mechanisms.

NUCLEIC ACIDS RESEARCH (2021)

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Article Multidisciplinary Sciences

METTL3 regulates heterochromatin in mouse embryonic stem cells

Wenqi Xu et al.

Summary: METTL3 regulates mouse embryonic stem-cell heterochromatin, critical for silencing retroviral elements and mammalian development. Through m(6)A methylation, METTL3 modulates integrity of IAP heterochromatin.

NATURE (2021)

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Article Multidisciplinary Sciences

N6-methyladenosine RNA modification suppresses antiviral innate sensing pathways via reshaping double-stranded RNA

Weinan Qiu et al.

Summary: This study demonstrates that during viral infection, the m(6)A methyltransferase METTL3 translocates to the cytoplasm to increase viral RNA m(6)A modification, diminish viral dsRNA content, and thereby dampen the RIG/MDA5-induced anti-viral immunity.

NATURE COMMUNICATIONS (2021)

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Article Oncology

N6-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation

Yuanming Cheng et al.

Summary: The study revealed the crucial role of m(6)A in myeloid leukemia, where it maintains cell survival and the undifferentiated state necessary for leukemia maintenance through the formation of nuclear YTHDC1-m(6)A condensates.

CANCER CELL (2021)

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Review Oncology

N6-methyladenosine methyltransferases: functions, regulation, and clinical potential

Wei Huang et al.

Summary: This review summarizes the role of N6-methyladenosine in the transcriptome and discusses the function of m6A methyltransferases in regulating cancer biology. The article highlights the use of m6A methyltransferases in mediating therapy resistance and discusses the clinical potential of targeted strategies.

JOURNAL OF HEMATOLOGY & ONCOLOGY (2021)

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Article Biochemistry & Molecular Biology

m6A RNA methylation regulates promoter-proximal pausing of RNA polymerase II

Junaid Akhtar et al.

Summary: m(6)A RNA modification regulates RNAP II pausing in Drosophila cells, affecting pause release, Ser2P occupancy, and nascent RNA transcription. The m(6)A-mediated gene regulation adds another layer to the control of gene expression.

MOLECULAR CELL (2021)

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Article Biochemistry & Molecular Biology

Enhancer RNA m6A methylation facilitates transcriptional condensate formation and gene activation

Joo-Hyung Lee et al.

Summary: The study reveals the heavy but selective deposition of m6A on nascent RNAs produced by transcription regulatory elements, and shows that m6A-eRNAs mark highly active enhancers by recruiting YTHDC1 and promoting condensate formation. This mechanism plays broad roles in enhancer activation and gene transcriptional control.

MOLECULAR CELL (2021)

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Article Biochemistry & Molecular Biology

Human MettL3-MettL14 RNA adenine methyltransferase complex is active on double-stranded DNA containing lesions

Dan Yu et al.

Summary: The MettL3-MettL14 methyltransferase complex is active in repairing DNA damage by UV and X-ray exposure. N6-methyladenine (N6mA) reduces misincorporation of 8-oxo-guanine (8-oxoG) during DNA repair, and inhibits excision of N6mA by the adenine DNA glycosylase when 8-oxoG is incorporated. The N6mA reader domain of YTHDC1 binds to N6mA at damaged DNA sites, providing a potential mechanism for N6mA writer and reader proteins in DNA repair.

NUCLEIC ACIDS RESEARCH (2021)

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Article Multidisciplinary Sciences

Hakai is required for stabilization of core components of the m6A mRNA methylation machinery

Praveen Bawankar et al.

Summary: The E3 ligase Hakai is a conserved component of the m(6)A methyltransferase complex in Drosophila and human cells. Depletion of Hakai results in reduced m(6)A levels and altered functions, affecting sex determination in Drosophila.

NATURE COMMUNICATIONS (2021)

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Article Multidisciplinary Sciences

Arginine methylation of METTL14 promotes RNA N6-methyladenosine modification and endoderm differentiation of mouse embryonic stem cells

Xiaona Liu et al.

Summary: The arginine methylation of METTL14 stabilizes the binding of the m(6)A methyltransferase complex to its substrate RNA, thereby promoting global m(6)A modification and mESC endoderm differentiation. The crosstalk between protein methylation and RNA methylation in gene expression is highlighted. The interaction of METTL3/METTL14 with WTAP and substrate RNA is enhanced by arginine methylation of METTL14 at R255 by PRMT1, promoting m(6)A methylation activity of the complex.

NATURE COMMUNICATIONS (2021)

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Article Multidisciplinary Sciences

A single m6A modification in U6 snRNA diversifies exon sequence at the 5' splice site

Yuma Ishigami et al.

Summary: The modification of N-6-methyladenosine on spliceosomal U6 snRNA facilitates efficient recognition of the splice sites through cooperation with U5 snRNA, allowing for variation in the 5' exon sequence and contributing to protein sequence diversity.

NATURE COMMUNICATIONS (2021)

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Article Genetics & Heredity

N-6-methyladenosine regulates the stability of RNA:DNA hybrids in human cells

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