YTHDF2 Binds to 5-Methylcytosine in RNA and Modulates the Maturation of Ribosomal RNA

Dai, Xiaoxia; Gonzalez, Gwendolyn Michelle; Li, Lin; Li, Jie; You, Changjun; Miao, Weili; Hu, Jiawei; Fu, Lijuan; Zhao, Yue; Li, Ruidong; Li, Lichao; Chen, Xuemei; Xu, Yanhui; Gu, Weifeng; Wang, Yinsheng

doi:10.1021/acs.analchem.9b04505

Cited by 66 publications

(49 citation statements)

References 56 publications

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“…There is no mammalian protein domain currently known to bind N4mC; but MettL15 introduces N4mC in rRNA ( 62 ). However, the DUF55 domain of human thymocyte nuclear protein 1 (THYN1; also known as Thy28) shares a structural fold with the YTH domain ( 63 , 64 ), and has been suggested to bind DNA containing modified cytosine ( 65 ), while YTHDF2 binds 5mC in RNA ( 66 ). We note that the methyl groups of N4mC and N6mA share their location on the exocyclic amino groups of cytosine (at N4) and adenine (at N6) (Figure 6D ), and the MTases responsible for these two types of amino (N4-cytosine and N6-adenine) methylation belong to the same MTase family group ( 4 , 25 ).…”

Section: Resultsmentioning

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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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: Resultsmentioning

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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“…This lower affinity, coupled to the scarcity of both marks in mRNAs, leaves the actual occurrence and phenotypic impact of this "integration" as a question still to be answered. If confirmed, also other YTH domain-family proteins could behave similarly (Dai et al 2018b;Seo and Kleiner 2020;Dai et al 2020), as might be expected given their observed redundancy (Zaccara and Jaffrey 2020). One may thus wonder how these mechanisms could induce or affect pathological states (Meier et al 2016;Kadumuri and Janga 2018;Christofi and Zaravinos 2019;Huang et al 2020b).…”

Section: Interplaymentioning

confidence: 55%

“…Recently, new data Cold Spring Harbor Laboratory Press on January 3, 2021 -Published by rnajournal.cshlp.org Downloaded from suggested that different epitranscriptomic marks could coexist on the same transcript, and that a potentially widespread cooperative and competitive interplay could control the RNA fate, likely through RBPs (Dassi 2017). While the extent of this crosstalk is still unclear, several research groups described potential, mostly correlative, occurrences of such mechanisms (Li et al 2017a;Xiang et al 2018;Sokołowski et al 2018;Wei et al 2018a;Dai et al 2018b;Huang et al 2019;Seo and Kleiner 2020;Dai et al 2020). For instance, both m 6 A and m 5 C methylation sites were found in a specific region of the p21 mRNA.…”

Section: Interplaymentioning

confidence: 99%

“…On the other end, RBPs controlling the lifecycle of RNA modifications appear to interact with marks other than their canonical one. For instance, the YTHDF2 m 6 A reader may "integrate" epitranscriptomics marks by also reading m 1 A and m 5 C (Dai et al 2018b;Lao and Barron 2019;Seo and Kleiner 2020;Dai et al 2020). A conserved residue of YTHDF2 (Trp 432 ) is required for the recognition of all the three modifications, albeit the affinities for m 1 A and m 5 C are lower than those for m 6 A.…”

Section: Interplaymentioning

confidence: 99%

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A mark of disease: how mRNA modifications shape genetic and acquired pathologies

Destefanis

Avşar

Groza

et al. 2020

RNA

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RNA modifications have recently emerged as a widespread and complex facet of gene expression regulation. Counting more than 170 distinct chemical modifications with far-reaching implications for RNA fate, they are collectively referred to as the epitranscriptome. These modifications can occur in all RNA species, including messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). In mRNAs the deposition, removal, and recognition of chemical marks by writers, erasers and readers influence their structure, localization, stability, and translation. In turn, this modulates key molecular and cellular processes such as RNA metabolism, cell cycle, apoptosis, and others. Unsurprisingly, given their relevance for cellular and organismal functions, alterations of epitranscriptomic marks have been observed in a broad range of human diseases, including cancer, neurological and metabolic disorders. Here, we will review the major types of mRNA modifications and editing processes in conjunction with the enzymes involved in their metabolism and describe their impact on human diseases. We present the current knowledge in an updated catalog. We will also discuss the emerging evidence on the crosstalk of epitranscriptomic marks and what this interplay could imply for the dynamics of mRNA modifications. Understanding how this complex regulatory layer can affect the course of human pathologies will ultimately lead to its exploitation toward novel epitranscriptomic therapeutic strategies.

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“…Accumulating evidence showed that YTHDF2, as a member of m6A "readers", played a significant role in multiple diseases, such as hematopathy and cancers [19][20][21]. Besides, significant progress had been made in fully understanding the role of m6A modifications in mRNA decay [22], pre-ribosomal RNA (rRNA) processing [23], and so on. These mechanisms were associated with diverse physiological and pathological processes, such as regulating inflammatory response [24], inducing pluripotent stem cells [25], adipogenesis [19].…”

Section: Introductionmentioning

confidence: 99%

The biological function of m6A reader YTHDF2 and its role in human disease

Wang

2021

Cancer Cell Int

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N6-methyladenosine (m6A) modification is a dynamic and reversible post-transcriptional modification and the most prevalent internal RNA modification in eukaryotic cells. YT521-B homology domain family 2 (YTHDF2) is a member of m6A “readers” and its role in human diseases remains unclear. Accumulating evidence suggests that YTHDF2 is greatly implicated in many aspects of human cancers and non-cancers through various mechanisms. YTHDF2 takes a great part in multiple biological processes, such as migration, invasion, metastasis, proliferation, apoptosis, cell cycle, cell viability, cell adhesion, differentiation and inflammation, in both human cancers and non-cancers. Additionally, YTHDF2 influences various aspects of RNA metabolism, including mRNA decay and pre-ribosomal RNA (pre-rRNA) processing. Moreover, emerging researches indicate that YTHDF2 predicts the prognosis of different cancers. Herein, we focus on concluding YTHDF2-associated mechanisms and potential biological functions in kinds of cancers and non-cancers, and its prospects as a prognostic biomarker.

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YTHDF2 Binds to 5-Methylcytosine in RNA and Modulates the Maturation of Ribosomal RNA

Cited by 66 publications

References 56 publications

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

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

A mark of disease: how mRNA modifications shape genetic and acquired pathologies

The biological function of m6A reader YTHDF2 and its role in human disease

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