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Shi et al. Cell Death and Disease (2021) 12:346 https://doi.org/10.1038/s41419-021-03625-8 Cell Death & Disease REVIEW ARTICLE Open Access Linking the YTH domain to cancer: the importance of YTH family proteins in epigenetics Rongkai Shi1, Shilong Ying1, Yadan Li1,LiyuanZhu 1,XianWang2 and Hongchuan Jin1 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. ● Facts Is evaluating structural differences in YTH domains the potential direction for exploring and explaining fi ● The effects of YTH proteins on RNA metabolism are the complex phenomena in this eld? ● Is a highly selective YTH domain inhibitor a 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; different but overlap to some degree. ● The structure of the YTH domain helps YTHDF potential therapeutic agent for cancer? ● proteins recognize and bind m6A-containing Is the existing structural information about the YTH transcripts. domain useful for guiding the rational design of ● Structural crystallography studies have elaborated selective YTH domain inhibitors? the molecular basis of YTH domains to read m6A- modified RNA. Introduction ● YTH proteins have different targets in different Since the 1950s, nucleotides, which are the basic cancers and are involved in almost every aspect of molecular components of RNA, have been found to tumorigenesis and cancer progression. undergo a number of chemical modifications on their adenosine (A), guanosine (G), cytidine (C), and uridine Open questions (U) nucleosides. Over 100 kinds of RNA modifications, such as hm5C, m1A, and m6A, have been found and ● What is the precise unified model of YTH proteins these modifications can affect the biogenesis, structure, in the regulation of m6A modification? Are these and function of RNA in different ways; these mod- proteins different or redundant? ifications have been the hotspots in epigenetics in recent years and still have great potential for explora- tion. N6-methyladenosine (m6A) has been considered Correspondence: Hongchuan Jin ([email protected]) 1Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang, Sir Run Run the most prevalent and reversible modification of Shaw Hospital, Cancer Center, Zhejiang University, Hangzhou, China mRNA in eukaryotic cells since its initial discovery in 2 Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School the 1970s1. m6A modification is generally located in the of Zhejiang University, Hangzhou, China These authors contributed equally: Rongkai Shi, Shilong Ying consensus motif DRACH (D = G, A, or U; R = GorA; Edited by F. Pentimalli © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Shi et al. Cell Death and Disease (2021) 12:346 Page 2 of 14 H = A, C, or U), which is enriched in the coding YTHDF1-3 sequence (CDS) and 3′ untranslated region (3′ UTR) of YTHDF1 selectively recognizes m6A-modified mRNAs – RNA1 4. The regulation of m6A depends on three via the YTH domain, promotes their loading into the important factors, “writers”, “erasers”,and“readers”. ribosome, and interacts with initiation factors to facilitate “Writers” and “erasers” add and remove m6A mod- their translation via the N-terminal domain18. In addition ifications to and from RNA, respectively, while “read- to mediating translation initiation, YTHDF1 can also bind ers” recognize m6A and affect the fate of RNA. to the m6A site in the CDS of some mRNAs to assist with Generally, m6A reader proteins can be divided into translation elongation19. Additionally, some research has three classes, which use the YTH domain (YTH family indicated that YTHDF1 may sometimes mediate the tar- – proteins), m6A switch mechanism (hnRNPC, hnRNPG, get transcript’s stability20 22. It is worth mentioning that and hnRNPA2B1), or common RNA-binding domain YTHDF1 is of great importance in the field of neu- and its flanking regions (IGF2BPs and hnRNPA2B1) to roscience since it was reported to be capable of inducing bind m6A-containing transcripts5. In recent years, axon regeneration23, regulating axon guidance24, and writers and erasers have been actively researched6,and thereby facilitating learning and memory25 by enhancing recently, the focus has gradually turned to readers, the translation of specific transcripts. Conversely, especially YTH family proteins, due to the application YTHDF2 selectively binds m6A-modified RNA and reg- of several novel methods. m6A-seq, based on antibody- ulates its degradation by recruiting the CCR4-NOT mediated capture and massively parallel sequencing, complex to accelerate RNA deadenylation10,26,27. helpsusidentifym6Asitesatthetranscriptomelevel. Another YTHDF2-mediated RNA degradation mechan- In addition to traditional methods such as RIP-seq, new ism is endoribonucleolytic cleavage via HRSP12-mediated techniques such as CLIP-seq and PAR-CLIP, based on bridging of YTHDF2-bound RNAs to RNase P/MRP, combining immunoprecipitation with in vivo UV through which a subset of circular RNAs is selectively crosslinking enhanced by photoactivatable ribonucleo- downregulated in an m6A-dependent manner28. The P/ – sides, help us identify the targets of m6A readers7 10. Q/N-rich N-terminal domain of YTHDF2 is responsible These methods are shedding new light on RNA mod- for its function in RNA decay, while its aa 101–200 region ifications. Therefore, we attempt to review the regula- interacts with the SH domain of CNOT1, and its aa 1–100 tion of transcripts by YTH family proteins, the region is the HRSP12 binding region. In addition, structural basis of the YTH domain, and the association YTHDF3 interacts with YTHDF1 to help promote protein of YTH family proteins with human cancers. translation, and with YTHDF2 to affect the decay of methylated mRNA transcripts29. There is also a model of YTH family proteins recognize m6A and regulate m6A regulation in which pre-mRNA is first recognized by RNA processes YTHDF3, which acts as an assigner, and YTHDF1 and m6A modification is regulated by RNA methyl- YTHDF2 then competitively interact with YTHDF3, thus transferase complexes—writers—and demethylases— determining the fate of the mRNA transcript30. Impor- erasers. To catalyze N6-methyladenosine (m6A) RNA tantly, recent studies have revealed that YTHDFs can be methylation, methyltransferase-like 3 (METTL3) and involved in liquid-liquid phase separation by binding human methyltransferase-like 14 (METTL14) form a multi-m6A-modified mRNA scaffolds and then forming stable heterodimer core complex with Wilms tumor 1- YTHDF–m6A–mRNA complexes. These complexes then associated protein (WTAP), which enables the complex partition into phase-separated compartments such as P to localize to nuclear speckles enriched with pre-mRNA bodies, stress granules, or neuronal RNA granules to processing factors11,12. Additionally, other adaptor decide whether the mRNA should be degraded, trans- proteins, such as RBM15/15B, VIRMA, and ZC3H13, lated, or undergo other events. Especially in stress granule have been shown to be important for facilitating the formation, YTHDF proteins are critical in recruiting – function of the methyltransferase complex13 15. mRNA to stress granules. In addition, this phase separa- Regarding demethylases, only fat mass and obesity- tion is significantly enhanced by mRNAs that contain associated (FTO) and AlkB homolog 5 (ALKBH5) have multiple m6A motifs. In contrast to mRNAs containing a been found to be available to catalyze m6A demethyla- single m6A site, mRNAs containing multiple m6A sites tion thus far16,17. The YTH domain, the structural basis tend to act as scaffolds for the binding of YTHDF proteins for the recognition and binding of m6A-modified RNA, to juxtapose their low-complexity domains and initiate – enables a series of proteins such as YTHDF1-3 and phase separation31 34. Remarkably, given that YTH YTHDC1-2 to act as readers in the

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