Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain

Xu, Chao; Xiao, Wang; Liu, Ke; Roundtree, Ian A.; Tempel, W.; Li, Yanjun; Lu, Zhike; He, Chuan; Min, Jinrong

doi:10.1038/nchembio.1654

Cited by 604 publications

(666 citation statements)

References 31 publications

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“…In contrast, YTH domain family protein 1 (YTHDF1) exerts its role in promoting translation efficiency 27. In the meantime, the role of YTH domain‐containing protein 1 (YTHDC1) in regulating mRNA splicing has been revealed 28, 29. In 2017, Shi et al.…”

Section: The Discovery Of M6a and Its Functionmentioning

confidence: 99%

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

Wang

et al. 2018

J Cellular Molecular Medi

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As the most abundant and reversible RNA modification in eukaryotic cells, m6A triggers a new layer of epi‐transcription. M6A modification occurs through a methylation process modified by “writers” complexes, reversed by “erasers”, and exerts its role depending on various “readers”. Emerging evidence shows that there is a strong association between m6A and human diseases, especially cancers. Herein, we review bi‐aspects of m6A in regulating cancers mediated by the m6A‐associated proteins, which exert vital and specific roles in the development of various cancers. Generally, the m6A modification performs promotion or inhibition functions (dual role) in tumorigenesis and progression of various cancers, which suggests a new concept in cancer regulations. In addition, m6A‐targeted therapies including competitive antagonists of m6A‐associated proteins may provide a new tumour intervention in the future.

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Section: The Discovery Of M6a and Its Functionmentioning

confidence: 99%

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

Wang

et al. 2018

J Cellular Molecular Medi

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“…Defects of the m 6 A methyltransferase complex result in a battery of development problems in various eukaryotic species (Yue et al, 2015). The YTH domain proteins, the m 6 A readers, influence the stability, translation, and splicing of the m 6 A-containing mRNAs Wang et al, 2015;Xiao et al, 2016;Xu et al, 2014;Zhou et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

ALKBH1-Mediated tRNA Demethylation Regulates Translation

Liu¹,

Clark²,

Luo³

et al. 2016

Cell

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SummaryTransfer RNA (tRNA) is a central component of protein synthesis and cell signaling network. One salient feature of tRNA is its heavily modified status, which can critically impact its function. Here we show that mammalian ALKBH1 is a tRNA demethylase. It mediates the demethylation of N 1 -methyladenosine (m 1 A) in tRNAs. The ALKBH1-catalyzed demethylation of the target tRNAs results in attenuated translation initiation and their decreased usage in protein synthesis. This process is dynamic and responds to glucose availability to affect translation. Our results uncover reversible methylation of tRNA as a new regulatory mechanism of post-transcriptional gene expression. In briefReversible tRNA methylation helps translation respond to nutrient availability.

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“…3A). An aromatic cage, which is normally composed of 2-4 aromatic residues, is a signature feature of methylation reader proteins that recognize methylated lysine, arginine, and even N 6 -methyladenosine (14). Here, ZCWPW2 used 3 aromatic residues, namely Trp-30, Trp-41, and Phe-78, to read out the trimethyllysine (Fig.…”

Section: Zcwpw2 Morc3 and Morc4 Are Histone H3k4me3mentioning

confidence: 99%

“…We further determined the crystal structures of human ZCWPW2 and MORC3 CW domains in complex with H3K4me3 peptide and provide a structural explanation for the differences in the CW domain's histone binding abilities. Generally, an aromatic cage is a signature feature of methylation reader proteins that recognize methylated lysine, arginine, and even N 6 -methyladenosine (14), and it is normally composed of 2-4 aromatic residues. However, our case study of ZCWPW2 revealed that only the invariant tryptophan, a cage-forming residue of the CW domain, was essential for recognition of the methyllysine residue, whereas the other cage-forming residues play roles in enhancing binding or filtering methylation states.…”

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Family-wide Characterization of Histone Binding Abilities of Human CW Domain-containing Proteins

Liu

Tempel

Zhang

et al. 2016

Journal of Biological Chemistry

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Covalent modifications of histone N-terminal tails play a critical role in regulating chromatin structure and controlling gene expression. These modifications are controlled by histone-modifying enzymes and read out by histone-binding proteins. Numerous proteins have been identified as histone modification readers. Here we report the family-wide characterization of histone binding abilities of human CW domain-containing proteins. We demonstrate that the CW domains in ZCWPW2 and MORC3/4 selectively recognize histone H3 trimethylated at Lys-4, similar to ZCWPW1 reported previously, while the MORC1/2 and LSD2 lack histone H3 Lys-4 binding ability. Our crystal structures of the CW domains of ZCWPW2 and MORC3 in complex with the histone H3 trimethylated at Lys-4 peptide reveal the molecular basis of this interaction. In each complex, two tryptophan residues in the CW domain form the "floor" and "right wall," respectively, of the methyllysine recognition cage. Our mutation results based on ZCWPW2 reveal that the right wall tryptophan residue is essential for binding, and the floor tryptophan residue enhances binding affinity. Our structural and mutational analysis highlights the conserved roles of the cage residues of CW domain across the histone methyllysine binders but also suggests why some CW domains lack histone binding ability.Chromatin structure is dynamically regulated by histone post-translational modifications, such as methylation, acetylation, phosphorylation, ubiquitination, and sumoylation (1). These post-translational modifications constitute the "histone code," which is written or erased by histone-modifying enzymes and recognized by histone code "reader" proteins (2-4).Histone methylation, such as lysine methylation at the ⑀-amino group at levels from mono-to trimethylation (me1-me3), has received extensive attention (5). A number of domains bind methylated histone tails. Prominent examples include the chromodomain, Tudor domain, MBT domain, PWWP domain, and PHD domain (4, 6, 7). The CW domain has recently been identified as a new member of the lysine methylation reader family (8 -11).The CW domain is a zinc binding domain, composed of ϳ50 amino acid residues with four conserved cysteine (C) and two conserved tryptophan (W) residues, and its name was derived from these conserved residues. CW domains are found in chromatin-associated proteins in animals and plants and grouped into 12 families based on sequence similarity (12). There are seven CW domain-containing proteins in humans, namely ZCWPW1, ZCWPW2, MORC1, MORC2, MORC3, MORC4, and LSD2 (Fig. 1A). Prior studies have shown that the CW domains of ZCWPW1 (8), MORC3 (10), and MORC4 (9) are readers of H3K4 3 methylated histones with differing preferences for histone H3K4 methylation states (i.e. ZCWPW1 and MORC3 preferentially recognize histone H3K4me3 (8, 10), whereas the CW domain of human MORC4 prefers dimethylated H3K4 (9)). The LSD2 CW domain is required for the demethylation function of LSD2 but does not bind to any H3K4 peptides (13). However, th...

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Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain

Cited by 604 publications

References 31 publications

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

ALKBH1-Mediated tRNA Demethylation Regulates Translation

Family-wide Characterization of Histone Binding Abilities of Human CW Domain-containing Proteins

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