CDK11 regulates pre-mRNA splicing by phosphorylation ofSF3B1

J 2022

CDK11 regulates pre-mRNA splicing by phosphorylation ofSF3B1

HLUCHÝ, Milan; Pavla GAJDUŠKOVÁ; Igor RUIZ DE LOS MOZOS; Michal RÁJECKÝ; Michael KLUGE et. al.

Základní údaje

Originální název

CDK11 regulates pre-mRNA splicing by phosphorylation ofSF3B1

Autoři

Vydání

NATURE, ENGLAND, NATURE PORTFOLIO, 2022, 0028-0836

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Německo

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 64.800

Kód RIV

RIV/00216224:14740/22:00126884

Organizační jednotka

Středoevropský technologický institut

DOI

https://doi.org/10.1038/s41586-022-05204-z

UT WoS

000854742900002

EID Scopus

2-s2.0-85138212060

Klíčová slova anglicky

Chromatin; Cyclin-Dependent Kinases; Phosphorylation; Ribonucleoprotein; U2 Small Nuclear; RNA Precursors; RNA Splicing; RNA Splicing Factors; Spliceosomes; Threonine

Štítky

14313010, CF PROT, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 4. 12. 2025 11:33, Mgr. Eva Dubská

Anotace

V originále

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.

Návaznosti

CZ.1.05/1.1.00/02.0068, interní kód MU

Název: CEITEC - středoevropský technologický institut (Akronym: CEITEC)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC - středoevropský technologický institut, 1.1 Evropská centra excelence

ED1.1.00/02.0068, projekt VaV

Název: CEITEC - central european institute of technology

EF16_025/0007381, projekt VaV

Název: Preklinická progrese nových organických sloučenin s cílenou biologickou aktivitou

GA21-19266S, projekt VaV

Název: Charakterizace kinazové aktivity cyklin dependentní kinázy 11 (CDK11), enzymu nezbytného pro růst nádorů

Investor: Grantová agentura ČR, Charakterizace kinazové aktivity cyklin dependentní kinázy 11 (CDK11)

LM2018130, projekt VaV

Název: Národní infrastruktura chemické biologie (Akronym: CZ-OPENSCREEN)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CZ-OPENSCREEN: National Infrastructure for Chemical Biology

MUNI/G/1129/2021, interní kód MU

Název: Development and use of CDK11 inhibitors for pilot characterization of the novel anti-cancer target

Investor: Masarykova univerzita, Development and use of CDK11 inhibitors for pilot characterization of the novel anti-cancer target, INTERDISCIPLINARY - Mezioborové výzkumné projekty

90127, velká výzkumná infrastruktura

Název: CIISB II

Citovat

HLUCHÝ, Milan; Pavla GAJDUŠKOVÁ; Igor RUIZ DE LOS MOZOS; Michal RÁJECKÝ; Michael KLUGE; Benedict-Tilman BERGER; Zuzana SLABÁ; David POTĚŠIL; Elena WEISS; Jernej ULE; Zbyněk ZDRÁHAL; Stefan KNAPP; Kamil PARUCH; Caroline C. FRIEDEL a Dalibor BLAŽEK. CDK11 regulates pre-mRNA splicing by phosphorylation ofSF3B1. NATURE. ENGLAND: NATURE PORTFOLIO, 2022, roč. 609, č. 7928, s. 829-834, 36 s. ISSN 0028-0836. Dostupné z: https://doi.org/10.1038/s41586-022-05204-z.

@article{2224578,
   author = {Hluchý, Milan and Gajdušková, Pavla and Ruiz de los Mozos, Igor and Rájecký, Michal and Kluge, Michael and Berger, BenedictandTilman and Slabá, Zuzana and Potěšil, David and Weiss, Elena and Ule, Jernej and Zdráhal, Zbyněk and Knapp, Stefan and Paruch, Kamil and Friedel, Caroline C. and Blažek, Dalibor},
   article_location = {ENGLAND},
   article_number = {7928},
   doi = {https://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},
   language = {eng},
   issn = {0028-0836},
   journal = {NATURE},
   title = {CDK11 regulates pre-mRNA splicing by phosphorylation ofSF3B1},
   url = {https://www.nature.com/articles/s41586-022-05204-z},
   volume = {609},
   year = {2022}
}

TY  - JOUR
ID  - 2224578
AU  - 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
PY  - 2022
TI  - CDK11 regulates pre-mRNA splicing by phosphorylation ofSF3B1
JF  - NATURE
VL  - 609
IS  - 7928
SP  - 829-834
EP  - 829-834
PB  - NATURE PORTFOLIO
SN  - 00280836
KW  - Chromatin
KW  - Cyclin-Dependent Kinases
KW  - Phosphorylation
KW  - Ribonucleoprotein
KW  - U2 Small Nuclear
KW  - RNA Precursors
KW  - RNA Splicing
KW  - RNA Splicing Factors
KW  - Spliceosomes
KW  - Threonine
UR  - https://www.nature.com/articles/s41586-022-05204-z
N2  - 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.
ER  -

HLUCHÝ, Milan; Pavla GAJDUŠKOVÁ; Igor RUIZ DE LOS MOZOS; Michal RÁJECKÝ; Michael KLUGE; Benedict-Tilman BERGER; Zuzana SLABÁ; David POTĚŠIL; Elena WEISS; Jernej ULE; Zbyněk ZDRÁHAL; Stefan KNAPP; Kamil PARUCH; Caroline C. FRIEDEL a Dalibor BLAŽEK. CDK11 regulates pre-mRNA splicing by phosphorylation ofSF3B1. \textit{NATURE}. ENGLAND: NATURE PORTFOLIO, 2022, roč.~609, č.~7928, s.~829-834, 36 s. ISSN~0028-0836. Dostupné z: https://doi.org/10.1038/s41586-022-05204-z.

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