Mouse nuclear RNAi-defective 2 promotes splicing of weak 5′ splice sites

Author:

Flemr Matyas,Schwaiger Michaela,Hess Daniel,Iesmantavicius Vytautas,Ahel Josip,Tuck Alex Charles,Mohn Fabio,Bühler MarcORCID

Abstract

Removal of introns during pre-mRNA splicing, which is central to gene expression, initiates by base pairing of U1 snRNA with a 5′ splice site (5′SS). In mammals, many introns contain weak 5′SSs that are not efficiently recognized by the canonical U1 snRNP, suggesting alternative mechanisms exist. Here, we develop a cross-linking immunoprecipitation coupled to a high-throughput sequencing method, BCLIP-seq, to identify NRDE2 (nuclear RNAi-defective 2), and CCDC174 (coiled-coil domain-containing 174) as novel RNA-binding proteins in mouse ES cells that associate with U1 snRNA and 5′SSs. Both proteins bind directly to U1 snRNA independently of canonical U1 snRNP-specific proteins, and they are required for the selection and effective processing of weak 5′SSs. Our results reveal that mammalian cells use noncanonical splicing factors bound directly to U1 snRNA to effectively select suboptimal 5′SS sequences in hundreds of genes, promoting proper splice site choice, and accurate pre-mRNA splicing.

Funder

Swiss National Science Foundation

National Center of Competence in Research RNA and Disease

Novartis Research Foundation

Publisher

Cold Spring Harbor Laboratory

Subject

Molecular Biology

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