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Review
. 2021 Apr 1;12(4):346.
doi: 10.1038/s41419-021-03625-8.

Linking the YTH domain to cancer: the importance of YTH family proteins in epigenetics

Rongkai Shi #  1 , Shilong Ying #  1 , Yadan Li  1 , Liyuan Zhu  1 , Xian Wang  2 , Hongchuan Jin  3
Affiliations
Review

Linking the YTH domain to cancer: the importance of YTH family proteins in epigenetics

Rongkai Shi et al. Cell Death Dis. .

Abstract

N6-methyladenosine (m6A), the most prevalent and reversible modification of mRNA in mammalian cells, has recently been extensively studied in epigenetic regulation. YTH family proteins, whose YTH domain can recognize and bind m6A-containing RNA, are the main "readers" of m6A modification. YTH family proteins perform different functions to determine the metabolic fate of m6A-modified RNA. The crystal structure of the YTH domain has been completely resolved, highlighting the important roles of several conserved residues of the YTH domain in the specific recognition of m6A-modified RNAs. Upstream and downstream targets have been successively revealed in different cancer types and the role of YTH family proteins has been emphasized in m6A research. This review describes the regulation of RNAs by YTH family proteins, the structural features of the YTH domain, and the connections of YTH family proteins with human cancers.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Model of YTH family proteins modulating m6A-containing RNAs.
In cell nucleus, “writers” and “erasers” add and remove m6A modifications to and from RNA. YTHDC1 regulates splicing and mediates the export of m6A-containing mRNAs by recruiting SRSF3, while blocking SRSF10 mRNA binding. In cytoplasm, YTHDF1 recognizes m6A-containing mRNAs and promotes its translation initiation and elongation. And the m6A-containing mRNAs can also be recognized by YTHDF2, which promotes their degradation through two pathways, CCR4-NOT complex-mediated deadenylation and HRSP12-mediated endoribonucleolytic cleavage. YTHDF3 interacts with YTHDF1 and YTHDF2 to accelerate metabolism of m6A-modified mRNAs. YTHDC2 mainly functions to regulate the switch from mitosis to meiosis by interacting with MEIOC. YTHDC2 interacts with XRN1, UPF1, and MOV10 to destabilize its target RNAs. Also, the binding of YTHDC2 to the 18S rRNA and its 3′-5′ RNA helicase activity facilitates the translation of its target RNAs.
Fig. 2
Fig. 2. The YTH domain is usually located in the C terminus of proteins and is rich in basic amino acid residues for RNA binding.
A Schematic representation of the protein structure of human YTH domain-containing proteins (YTHDC1, YTHDC2, YTHDF1, YTHDF2, and YTHDF3). B, C The electrostatic potential surface of the YTH domains of YTHDC1 and YTHDF1 in complex with m6A-containing oligonucleotides is represented by PyMOL 2.0. Positive charges are colored blue, neutral charges are white, and negative charges are red.
Fig. 3
Fig. 3. The conserved aromatic residues and basic residues in the YTH domain are responsible for methylated adenosine (m6A) recognition and binding, respectively.
A Superposition of the complex structures of the YTHDC1 YTH domain (YTH-YTHDC1)-m6A (pink), YTH-YTHDF1-m6A (green), YTH-YTHDF2-m6A (yellow), and YTH-YTHDF3-m6A (pale green), showing the conserved aromatic cage for specific recognition of the methyl group of m6A. Both the residues in the aromatic cage of YTHDC1 and the 6-methylated adenine base (m6A) are shown in the model as pink sticks, and the counterparts in YTHDF1, YTHDF2, and YTHDF3 are shown in the model as green, yellow, and pale green sticks, respectively. In addition, the adenine base always forms three hydrogen bonds with adjacent residues (cyan sticks), which is essential for the binding between m6A and YTH domains. The hydrogen bonds are labeled with dashed lines. The corresponding PDB IDs are 4R3I, 4RCJ, 4RDN, and 6ZOT. B Four basic residues, R411, K416, R441, and R527, on the surface of the YTHDF2 YTH domain, are critical for binding to the RNA backbone. C Superposition of the YTH domains of YTHDC1 (pink cartoon), YTHDC2 (cyan cartoon), YTHDF1 (green cartoon), YTHDF2 (yellow cartoon), and YTHDF3 (pale green cartoon). The four basic residues are highly conserved in these human YTH proteins. The basic residues R411, K416, R441, and R527 in YTHDF2 and their corresponding residues in the YTH domains of YTHDC1, YTHDC2, YTHDF1, and YTHDF3 are shown as yellow, pink, cyan, green, and pale green sticks.
Fig. 4
Fig. 4. Structural comparison of YTHDC1 and YTHDF1 reveals the structural basis for the discriminative recognition of the nucleotide preceding the m6A mark by YTHDC1.
The YTHDC1-G(m6A) and YTHDF1-G(m6A) complexes are shown in the model as pink and green sticks, and the difference interactions between YTHDC1 and YTHDF1 with the G-1 nucleotide are highlighted with yellow dashed lines.
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