A study of SMD2 reads pseudouridines to regulate mRNA splicing and promote tumorigenesis

Description

Pseudouridines (Ψ) in mRNA are linked to alternative splicing, but their regulatory mechanisms remain unclear due to the lack of identified reader proteins. Here, we identify SMD2, a core spliceosomal component, as a direct Ψ reader. Using in vitro and ex vivo assays, we show that SMD2 preferentially binds Ψ over unmodified uridines. SMD2 collaborates with PUS family enzymes to regulate alternative splicing by binding Ψ near exon-intron boundaries, modulating the splicing of numerous pre-mRNAs. Notably, the gene encoding SMD2, SNRPD2, is overexpressed across multiple cancers and is essential for tumor cell proliferation through the maturation of key transcripts. These findings uncover a direct mechanistic link between Ψ and spliceosomal function, establishing SMD2 as a critical regulator of Ψ-mediated splicing and a potential cancer therapeutic target.The original images have been uploaded according to their corresponding figure numbers.

Institutions

• Tongji University

  Shanghai, Shanghai

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