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Interaction of CDK12 with NXF1 is a new node for the linking mechanism between transcription and transportation of mRNA.
Ebara, Shunsuke; Yoshida, Misaki; Yamakawa, Hiroko; Shimokawa, Kenichiro; Inoue, Yasumichi; Tauchi, Hiroshi; Morishita, Daisuke.
Afiliación
  • Ebara S; Department of Biological Sciences, Faculty of Science, Ibaraki University, Bunkyo 2-1-1, Mito, Ibaraki, 310-8512, Japan; Chordia Therapeutics Inc., Kanagawa, 251-0012, Japan.
  • Yoshida M; Chordia Therapeutics Inc., Kanagawa, 251-0012, Japan.
  • Yamakawa H; Department of Biological Sciences, Faculty of Science, Ibaraki University, Bunkyo 2-1-1, Mito, Ibaraki, 310-8512, Japan; Chordia Therapeutics Inc., Kanagawa, 251-0012, Japan.
  • Shimokawa K; Chordia Therapeutics Inc., Kanagawa, 251-0012, Japan.
  • Inoue Y; Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan.
  • Tauchi H; Department of Biological Sciences, Faculty of Science, Ibaraki University, Bunkyo 2-1-1, Mito, Ibaraki, 310-8512, Japan. Electronic address: hiroshi.tauchi.sci@vc.ibaraki.ac.jp.
  • Morishita D; Chordia Therapeutics Inc., Kanagawa, 251-0012, Japan. Electronic address: daisuke.morishita@chordiatherapeutics.com.
Biochem Biophys Res Commun ; 735: 150608, 2024 Aug 28.
Article en En | MEDLINE | ID: mdl-39270556
ABSTRACT
The transcription and transportation of mRNA are coupled processes; however, the mechanisms linking these processes remain unclear. Additionally, the significance of this connection in cancer drug development is poorly understood. To address these issues, we investigated the role of CDK12 kinase, which regulates RNA transcription through the phosphorylation of RNA polymerase II (Pol II) and has a repeated serine-arginine dipeptide (RS domain) involved in mRNA transport. Despite the anticipated uniqueness of CDK12 function, the mechanism by which CDK12 bridges and manages mRNA transcription and transport has not been fully analyzed. Our study revealed that CDK12 interacts with NXF1, a key molecule involved in the export of mRNA from the nucleus to the cytosol. Although CDK12 does not phosphorylate NXF1, we found that NXF1 unexpectedly stabilized the CDK12 protein, suggesting that NXF1 mRNA export activity indirectly affects mRNA transcriptional activity by modifying the protein level of CDK12. Furthermore, CDK12 recruited other essential RNA transporters, specifically the exon junction complex (EJC) and THO complexes, into the CDK12-NXF1 axis through its kinase activity. These observations provide insights into the mechanisms linking mRNA transcription and transport through the formation of a novel CDK12-NXF1 complex that involves EJC and THO. Importantly, the expression level of NXF1 influences sensitivity to CDK12 inhibitors, which are emerging as novel anti-cancer drug candidates. This highlights the importance of considering the relationship between mRNA transcription and transport when targeting RNA transcription in cancer therapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Biochem Biophys Res Commun Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Biochem Biophys Res Commun Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos