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Updated: Sep 24, 2025

Tuning Degradation to Achieve Specific and Efficient Protein Depletion
Published on: July 20, 2019
P-TEFb is degraded by Siah1/2 in quiescent cells
Fang Huang1, Yongmei Feng2, B Matija Peterlin1
1Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
Abstract:
P-TEFb, composed of CycT1 and CDK9, regulates the elongation of transcription by RNA polymerase II. In proliferating cells, it is regulated by 7SK snRNA in the 7SK snRNP complex. In resting cells, P-TEFb is absent, because CycT1 is dephosphorylated, released from CDK9 and rapidly degraded. In this study, we identified the mechanism of this degradation. We mapped the ubiquitination and degradation of free CycT1 to its N-terminal region from positions 1 to 280. This region is ubiquitinated at six lysines, where E3 ligases Siah1 and Siah2 bind and degrade these sequences. Importantly, the inhibition of Siah1/2 rescued the expression of free CycT1 in proliferating as well as resting primary cells. We conclude that Siah1/2 are the E3 ligases that bind and degrade the dissociated CycT1 in resting, terminally differentiated, anergic and/or exhausted cells.
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