Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 43, Issue 9, Pages 451-471Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/10985549.2023.2239694
Keywords
CHIP; STUB1; ubiquitination; CDK9; P-TEFb complex; transcription; RNA polymerase II; >
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This study reveals the important role of STUB1 in regulating the overall level of CDK9 and P-TEFb complex. STUB1 acts as a ubiquitin E3 ligase for the proteasomal degradation of CDK9. CyclinT1 protects CDK9 from STUB1-mediated degradation through binding to the same region of CDK9. Knockdown of STUB1 enhances CDK9 expression, leading to increased P-TEFb complex formation and transcriptional activation of diverse target genes.
Positive transcription elongation factor b (P-TEFb) regulates expression of diverse sets of genes within mammalian cells that have implications in several human disease pathogeneses. However, mechanisms of functional regulation of P-TEFb complex through regulation of its stability are poorly known. In this study, we show an important role of C-terminus of Hsc70-interacting protein (CHIP aka STUB1) in regulation of overall level of CDK9 and thus P-TEFb complex within mammalian cells. STUB1 acts as a ubiquitin E3 ligase for proteasomal degradation of CDK9 involving N-terminal lysine 3 (K3) residue. Whereas, overexpression of STUB1 enhances, its knockdown reduces overall CDK9 degradation kinetics within mammalian cells. Interestingly, owing to the same region of binding within CDK9, CyclinT1 protects CDK9 from STUB1-mediated degradation. Factors that cooperatively bind with CyclinT1 to form functional complex also protects CDK9 from degradation by STUB1. Knockdown of STUB1 enhances CDK9 expression and thus P-TEFb complex formation that leads to global increase in RNA polymerase II CTD phosphorylation and transcriptional activation of diverse P-TEFb target genes. Thus, we describe an important functional role of STUB1 in regulation of transcription through modulation of overall level of P-TEFb complex formation within mammalian cells.
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