CDK11 regulates pre-mRNA splicing by phosphorylation ofSF3B1

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Authors

HLUCHÝ Milan GAJDUŠKOVÁ Pavla RUIZ DE LOS MOZOS Igor RÁJECKÝ Michal KLUGE Michael BERGER Benedict-Tilman SLABÁ Zuzana POTĚŠIL David WEISS Elena ULE Jernej ZDRÁHAL Zbyněk KNAPP Stefan PARUCH Kamil FRIEDEL Caroline C. BLAŽEK Dalibor

Year of publication 2022
Type Article in Periodical
Magazine / Source NATURE
MU Faculty or unit

Central European Institute of Technology

Citation
Web https://www.nature.com/articles/s41586-022-05204-z
Doi http://dx.doi.org/10.1038/s41586-022-05204-z
Keywords Chromatin; Cyclin-Dependent Kinases; Phosphorylation; Ribonucleoprotein; U2 Small Nuclear; RNA Precursors; RNA Splicing; RNA Splicing Factors; Spliceosomes; Threonine
Description RNA splicing, the process of intron removal from pre-mRNA, is essential for the regulation of gene expression. It is controlled by the spliceosome, a megadalton RNA-protein complex that assembles de novo on each pre-mRNA intron through an ordered assembly of intermediate complexes(1,2). Spliceosome activation is a major control step that requires substantial protein and RNA rearrangements leading to a catalytically active complex(1-5). Splicing factor 3B subunit 1 (SF3B1) protein-a subunit of the U2 small nuclear ribonucleoprotein(6)-is phosphorylated during spliceosome activation(7-)(10), but the kinase that is responsible has not been identified. Here we show that cyclin-dependent kinase 11 (CDK11) associates with SF3B1 and phosphorylates threonine residues at its N terminus during spliceosome activation. The phosphorylation is important for the association between SF3B1 and U5 and U6 snRNAs in the activated spliceosome, termed the B(act )complex, and the phosphorylation can be blocked by OTS964, a potent and selective inhibitor of CDK11. Inhibition of CDK11 prevents spliceosomal transition from the precatalytic complex B to the activated complex B-act and leads to widespread intron retention and accumulation of non-functional spliceosomes on pre-mRNAs and chromatin. We demonstrate a central role of CDK11 in spliceosome assembly and splicing regulation and characterize OTS964 as a highly selective CDK11 inhibitor that suppresses spliceosome activation and splicing.
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