CDK11 requires a critical activator SAP30BP to regulate pre‐mRNA splicing

• Published in: The EMBO journal 2023-12, Vol.42 (24), p.e114051-n/a
• Main Authors: Wang, Changshou, Xu, Lin, Du, Chen, Yun, Hao, Wang, Keyun, Liu, Hui, Ye, Mingliang, Fan, Jing, Zhou, Yu, Cheng, Hong
• Format: Article
• Language: English
• Subjects: Assembly; Cancer; Cancer therapies; CDK11; Cell cycle; Cell Division; cyclin L; Cyclins; Cyclins - genetics; Cyclins - metabolism; Gene expression; Gene regulation; Homeostasis; Kinases; Phosphorylation; pre‐mRNA splicing; RNA Precursors - genetics; RNA Precursors - metabolism; RNA Splicing; SAP30BP; Splicing factors; Transcription factors
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.2023114051

CDK11 is an emerging druggable target for cancer therapy due to its prevalent roles in phosphorylating critical transcription and splicing factors and in facilitating cell cycle progression in cancer cells. Like other cyclin‐dependent kinases, CDK11 requires its cognate cyclin, cyclin L1 or cyclin L2, for activation. However, little is known about how CDK11 activities might be modulated by other regulators. In this study, we show that CDK11 forms a tight complex with cyclins L1/L2 and SAP30BP, the latter of which is a poorly characterized factor. Acute degradation of SAP30BP mirrors that of CDK11 in causing widespread and strong defects in pre‐mRNA splicing. Furthermore, we demonstrate that SAP30BP facilitates CDK11 kinase activities in vitro and in vivo, through ensuring the stabilities and the assembly of cyclins L1/L2 with CDK11. Together, these findings uncover SAP30BP as a critical CDK11 activator that regulates global pre‐mRNA splicing. Synopsis CDK11 together with its cognate cyclins L1/L2 is involved in gene regulation and cell cycle control via phosphorylation of transcription and splicing factors. Here, SAP30BP is uncovered as another key CDK11/Cyclin L activator critical for pre‐mRNA splicing. CDK11 forms a tight complex with cyclins L1/L2 and SAP30BP. SAP30BP and CDK11 play highly similar roles in global pre‐mRNA splicing. CDK11 requires SAP30BP for kinase activity in vitro and in vivo. SAP30BP ensures stabilities and assembly of cyclins L1/L2 with CDK11. SAP30BP forms a tight complex with CDK11‐cyclins L1/L2, ensuring the stabilities and assembly of cyclins L1/L2 with CDK11.