Acetylation of cyclin T1 regulates the equilibrium between active and inactive P-TEFb in cells.
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-kappaB-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.
Cho
Sungyoo
S
Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158, USA.
Schroeder
Sebastian
S
Kaehlcke
Katrin
K
Kwon
Hye-Sook
HS
Pedal
Angelika
A
Herker
Eva
E
Schnoelzer
Martina
M
Ott
Melanie
M
D000107:Acetylation; D000595:Amino Acid Sequence; D002460:Cell Line; D056906:Cyclin T; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D011485:Protein Binding; D012342:RNA, Small Nuclear / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D014157:Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
C503684:CCNT1 protein, human; D056906:Cyclin T; D016213:Cyclins; C476123:HEXIM1 protein, human; D012342:RNA, Small Nuclear; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D042925:Positive Transcriptional Elongation Factor B; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9