Acetylation of cyclin T1 regulates the equilibrium between active and inactive P-TEFb in cells

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Abstract
The elongation competence of the RNA polymerase II complex is critically dependent on the positive transcription elongation factor b (P‐TEFb). P‐TEFb exists in two forms in cells, an active form composed of cyclin T1 and CDK9 and an inactive form, in which cyclin T1/CDK9 is sequestered by Hexim1 and 7SK snRNA. Here, we report that partitioning of active and inactive P‐TEFb is regulated by acetylation of cyclin T1. Cyclin T1 acetylation triggers dissociation of Hexim1 and 7SK snRNA from cyclin T1/CDK9 and activates the transcriptional activity of P‐TEFb. This activation is lost in P‐TEFb complexes containing cyclin T1 that can no longer be acetylated. An acetylation‐deficient cyclin T1 mutant dominantly suppresses NF‐κB‐mediated activation of the interleukin‐8 promoter but continues to synergize normally with the HIV Tat protein to transactivate the HIV long terminal repeat. These findings support the model that acetylation of cyclin T1 serves as a physiological switch that liberates P‐TEFb from its endogenous inhibitors Hexim1 and 7SK snRNA, but is not required for the cooperative action with HIV Tat.