Promoter clearance and transcriptional processivity in eukaryotic cells are fundamentally regulated by the phosphorylation of the carboxy-terminal domain of RNA polymerase II (RNAPII). One of the kinases that essentially performs this function is P-TEFb (positive transcription elongation factor b), which is composed of cyclin-dependent kinase 9 (CDK9) associated with members of the cyclin T family. Here we show that cellular GCN5 and P/CAF, members of the GCN5-related N-acetyltransferase family of histone acetyltransferases, regulate CDK9 function by specifically acetylating the catalytic core of the enzyme and, in particular, a lysine that is essential for ATP coordination and the phosphotransfer reaction. Acetylation markedly reduces both the kinase function and transcriptional activity of P-TEFb. In contrast to unmodified CDK9, the acetylated fraction of the enzyme is specifically found in the insoluble nuclear matrix compartment. Acetylated CDK9 associates with the transcriptionally silent human immunodeficiency virus type 1 provirus; upon transcriptional activation, it is replaced by the unmodified form, which is involved in the elongating phase of transcription marked by Ser2-phosphorylated RNAPII. Given the conservation of the CDK9 acetylated residues in the catalytic task of virtually all CDK proteins, we anticipate that this mechanism of regulation might play a broader role in controlling the function of other members of this kinase family.
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|Titolo:||Acetylation of conserved lysines in the catalytic core of cyclin-dependent kinase 9 inhibits kinase activity and regulates transcription.|
|Autori:||A., Sabò; M., Lusic; Cereseto, Anna; M., Giacca|
|Titolo del periodico:||MOLECULAR AND CELLULAR BIOLOGY|
|Anno di pubblicazione:||2008|
|Codice identificativo Scopus:||2-s2.0-41149145576|
|Codice identificativo Pubmed:||18250157|
|Codice identificativo WOS:||WOS:000254181400008|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1128/MCB.01557-07|
|Appare nelle tipologie:||03.1 Articolo su rivista (Journal article)|