SMD2 reads pseudouridines to regulate mRNA splicing and promote tumorigenesis

Area of Science:

• Molecular Biology
• RNA Biology
• Cancer Biology

Background:

• Pseudouridines (ψ) in mRNA are known to influence alternative splicing.
• The specific reader proteins and mechanisms mediating this regulation have remained largely unknown.
• Understanding these mechanisms is crucial for deciphering mRNA processing and its role in disease.

Purpose of the Study:

• To identify reader proteins that directly bind to pseudouridines (ψ) in mRNA.
• To elucidate the role of these reader proteins in spliceosomal function and alternative splicing.
• To investigate the potential of these proteins as therapeutic targets in cancer.

Main Methods:

• In vitro and ex vivo biochemical assays to detect RNA-protein interactions.
• Analysis of SMD2 binding preference for pseudouridine-modified RNA versus unmodified uridine.
• Investigation of SMD2's role in alternative splicing in human cells.
• Analysis of SNRPD2 gene expression in cancer tissues and its impact on tumor cell proliferation.

Main Results:

• SMD2, a core spliceosomal component, was identified as a direct reader of pseudouridines (ψ) in mRNA.
• SMD2 exhibits preferential binding to ψ-modified RNA over unmodified uridines.
• SMD2 collaborates with pseudouridine synthase (PUS) enzymes to regulate alternative splicing near exon-intron junctions.
• The gene encoding SMD2, SNRPD2, is overexpressed in multiple cancers and is critical for tumor cell proliferation via mRNA maturation modulation.

Conclusions:

• A direct mechanistic link between pseudouridines (ψ) and spliceosomal function has been established.
• SMD2 acts as a key regulator of ψ-mediated alternative splicing.
• SMD2 represents a promising therapeutic target for cancer treatment due to its role in mRNA maturation and tumor cell proliferation.