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1 Howard Hughes Medical Institute, The human immunodeficiency virus encodes the transcriptional
transactivator Tat, which binds to the transactivation response (TAR)
RNA stem-loop in the viral long terminal repeat (LTR) and increases
rates of elongation rather than initiation of transcription by RNA
polymerase II (Pol II). In this study, we demonstrate that Tat binds
directly to the cyclin-dependent kinase 7 (CDK7), which leads to
productive interactions between Tat and the CDK-activating kinase (CAK)
complex and between Tat and TFIIH. Tat activates the phosphorylation of
the carboxy-terminal domain (CTD) of Pol II by CAK in vitro. The
ability of CAK to phosphorylate the CTD can be inhibited specifically
by a CDK7 pseudosubstrate peptide that also inhibits transcriptional
activation by Tat in vitro and in vivo. We conclude that the
phosphorylation of the CTD by CAK is essential for Tat transactivation.
Our data identify a cellular protein that interacts with the activation
domain of Tat, demonstrate that this interaction is critical for the
function of Tat, and provide a mechanism by which Tat increases the
processivity of Pol II.
[Key Words:
HIV; transactivator Tat; phosphorylation; CTD; Pol II; CAK; CDK7]
GENES & DEVELOPMENT 11:2645-2657 © 1997 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/97 $5.00
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