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Roles of the phosphorylated SF3B1 in the activated spliceosome - experiment 1

ABSTRACT: SF3B1 is essential for assembly of B-complex spliceosome and activation of the Bact complex and undergoes dynamic phosphorylation and dephosphorylation during the splicing cycle. We have recently showed that the N-terminus of SF3B1 is phosphorylated during spliceosome activation by a little studied cyclin-dependent kinase 11 (CDK11) and remains hyperphosphorylated in catalytically active spliceosomes. However, little is known about the function of this N-terminal phosphorylation, about factors that “read” it, or about a spliceosome intermediate generated by CDK11 targeting. Here we demonstrate that CDK11 inhibition blocks spliceosome in a new intermediate during B to Bact transition. We now show that, phosphorylated SF3B1 N-terminus is crucial for binding of proteins during spliceosome activation.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: David Potesil

LAB HEAD: Zbynek Zdrahal

PROVIDER: PXD063160 | Pride | 2026-02-24

REPOSITORIES: Pride

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			Action	DRS
	4821_Lumos1_Lumos1_DDA_120min-IS_HCD-OT_2-5s_02_DMSO_01_01.raw	Raw
	4821_Lumos1_Lumos1_DDA_120min-IS_HCD-OT_2-5s_03_OTS_01_01.raw	Raw
	4821_Lumos1_Lumos1_DDA_120min-IS_HCD-OT_2-5s_05_DMSO_02_01.raw	Raw
	4821_Lumos1_Lumos1_DDA_120min-IS_HCD-OT_2-5s_06_OTS_02_01.raw	Raw
	4821_Lumos1_Lumos1_DDA_120min-IS_HCD-OT_2-5s_08_DMSO_03_01.raw	Raw

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Roles of the phosphorylated SF3B1 in the activated spliceosome - experiment 2

Project description:SF3B1 is essential for assembly of B-complex spliceosome and activation of the Bact complex and undergoes dynamic phosphorylation and dephosphorylation during the splicing cycle. We have recently showed that the N-terminus of SF3B1 is phosphorylated during spliceosome activation by a little studied cyclin-dependent kinase 11 (CDK11) and remains hyperphosphorylated in catalytically active spliceosomes. However, little is known about the function of this N-terminal phosphorylation, about factors that “read” it, or about a spliceosome intermediate generated by CDK11 targeting. Here we demonstrate that CDK11 inhibition blocks spliceosome in a new intermediate during B to Bact transition. We now show that, phosphorylated SF3B1 N-terminus is crucial for binding of proteins during spliceosome activation.

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Project 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 via an ordered assembly of intermediate complexes. Spliceosome activation is a major control step requiring dramatic protein and RNA rearrangements leading to a catalytically active complex. Splicing factor 3B subunit 1 (SF3B1) protein, a subunit of the U2 snRNP, is phosphorylated during spliceosome activation, but the responsible kinase 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 association of SF3B1 with U5 and U6 snRNAs in spliceosome activated Bact complex and it can be blocked by OTS964, a potent and selective inhibitor of CDK11. CDK11 inhibition 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 characterize OTS964 as a quality chemical biology probe for CDK11 and demonstrate a central role of CDK11 in spliceosome assembly and splicing regulation.

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CDK7 regulates pre-mRNA splicing via CDK11

Project description:Cyclin-dependent kinase 11 (CDK11) is essential for the regulation of pre-mRNA splicing by phosphorylating SF3B1, a core spliceosome component. This phosphorylation is a marker of the catalytically active spliceosome, so it is important to identify the mechanisms that regulate CDK11. Herein, we report that a small subset of CDK11 is phosphorylated on the activation T-loop threonine 595 (Thr595) and is associated with the activated spliceosome on chromatin in gene bodies. Mutational analyses revealed that Thr595 is essential for the formation of the active CDK11 complex with cyclin L and SAP30BP. CDK11 transiently associates with CDK7, a transcriptional kinase that also promotes the activation of other CDKs. The time course of the inhibition of CDK7 initially decreases transcription, but later produces unspliced pre-mRNAs. The dynamics of onset of the CDK7-mediated splicing defect correlates with the sequential dephosphorylation of CDK11 Thr595 and SF3B1. SILAC-based phospho-proteomics upon brief CDK11 inhibition identified SF3B1, CDC5L and ESS2 as CDK11 substrates, an overlap with the previously identified CDK7 substrates in the spliceosome. In summary, our study suggests that CDK7 likely acts via CDK11 Thr595 phosphorylation to regulate pre-mRNA splicing in cells. The identification of additional CDK11 substrates indicates its more complex role in spliceosome regulation.

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