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捷克共和国马萨里克大学Dalibor Blazek团队发现，CDK11通过SF3B1的磷酸化调节前体mRNA剪接。2022年9月14日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员发现，细胞周期蛋白依赖性激酶11（CDK11）与剪接因子3B亚单位1（SF3B1）结合，并在剪接体激活过程中对其N端苏氨酸残基进行磷酸化。磷酸化对SF3B1与激活的剪接体中的U5和U6 snRNA之间的结合很重要，称为Bact复合体，并且磷酸化可以被OTS964阻断，OTS964是CDK11的一种有效和选择性的抑制剂。抑制CDK11可以防止剪接体从催化前复合物B向激活复合物Bact过渡，并导致广泛的内含子保留和非功能性剪接体在前体mRNA和染色质上的积累。研究人员证明了CDK11在剪接体组装和剪接调节中的核心作用，并将OTS964描述为一种高选择性的CDK11抑制剂，可抑制剪接体的激活和剪接。

据了解，RNA剪接，即从前体mRNA上去除内含子的过程，对基因表达的调节至关重要。它由剪接体控制，剪接体是一种巨量级的RNA-蛋白质复合物，通过中间复合物的有序组装，在每个前体mRNA内含子上从新组装。剪接体的激活是一个主要的控制步骤，需要大量的蛋白质和RNA重新排列，从而形成一个有催化作用的复合体。SF3B1蛋白，U2小核糖核酸蛋白的一个亚单位，在剪接体激活过程中被磷酸化，但负责的激酶还没有被确定。

附：英文原文

Title: CDK11 regulates pre-mRNA splicing by phosphorylation of SF3B1

Author: Hluch, Milan, Gajdukov, Pavla, Ruiz de los Mozos, Igor, Rjeck, Michal, Kluge, Michael, Berger, Benedict-Tilman, Slab, Zuzana, Potil, David, Wei, Elena, Ule, Jernej, Zdrhal, Zbynk, Knapp, Stefan, Paruch, Kamil, Friedel, Caroline C., Blazek, Dalibor

Issue&Volume: 2022-09-14

Abstract: 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 complexes1,2. Spliceosome activation is a major control step that requires substantial protein and RNA rearrangements leading to a catalytically active complex1,2,3,4,5. Splicing factor 3B subunit 1 (SF3B1) protein—a subunit of the U2 small nuclear ribonucleoprotein6—is phosphorylated during spliceosome activation7,8,9,10, 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 Bact 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 Bact 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.

DOI: 10.1038/s41586-022-05204-z

Source: https://www.nature.com/articles/s41586-022-05204-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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