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

N6‐methyladenosine (m 6 A) and alternative polyadenylation (APA) are important regulators of gene expression in eukaryotes. Recently, it was found that m 6 A is closely related to APA. However, the molecular mechanism of this new APA regulation remains elusive. Here, we show that YTHDC1, a nuclear m...

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Veröffentlicht in:EMBO reports 2022-11, Vol.23 (11), p.n/a
Hauptverfasser: Chen, Liutao, Fu, Yonggui, Hu, Zhijie, Deng, Ke, Song, Zili, Liu, Susu, Li, Mengxia, Ou, Xin, Wu, Runze, Liu, Mian, Li, Rui, Gao, Shuiying, Cheng, Lin, Chen, Shangwu, Xu, Anlong
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Sprache:eng
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Zusammenfassung:N6‐methyladenosine (m 6 A) and alternative polyadenylation (APA) are important regulators of gene expression in eukaryotes. Recently, it was found that m 6 A is closely related to APA. However, the molecular mechanism of this new APA regulation remains elusive. Here, we show that YTHDC1, a nuclear m 6 A reader, can suppress proximal APA sites and produce longer 3′ UTR transcripts by binding to their upstream m 6 A sites. YTHDC1 can directly interact with the 3′ end processing factor FIP1L1 and interfere with its ability to recruit CPSF4. Binding to the m 6 A sites can promote liquid–liquid phase separation of YTHDC1 and FIP1L1, which may play an important role in their interaction and APA regulation. Collectively, YTHDC1 as an m 6 A “reader” links m 6 A modification with pre‐mRNA 3′ end processing, providing a new mechanism for APA regulation. Synopsis YTHDC1 inhibits proximal poly(A) sites by interfering with FIP1L1 – CPSF4 interaction, which results in mRNA transcripts with longer 3′ UTRs. YTHDC1 inhibits proximal APA sites in an m 6 A‐dependent manner. YTHDC1 regulates mRNA alternative polyadenylation by interacting with the 3′ processing protein FIP1L1. YTHDC1 interacts with FIP1L1 in nuclear condensates through liquid‐liquid phase separation (LLPS). Graphical Abstract YTHDC1 inhibits proximal poly(A) sites by interfering with FIP1L1 – CPSF4 interaction, which results in mRNA transcripts with longer 3′ UTRs.
ISSN:1469-221X
1469-3178
DOI:10.15252/embr.202254686