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Nucleic Acids Research 2005 33(22):7000-7010; doi:10.1093/nar/gki997
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Published online 23 December 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Oligomerization of HEXIM1 via 7SK snRNA and coiled-coil region directs the inhibition of P-TEFb

Dalibor Blazek1, Matjaz Barboric1, Jiri Kohoutek1, Irena Oven1,2 and B. Matija Peterlin1,*

1Departments of Medicine, Microbiology and Immunology, Rosalind Russell Medical Research Center, University of California at San Francisco San Francisco, CA 94143-0703, USA 2Biochemical Faculty, Department of Animal Science, University of Ljubljana Groblje 3, SI-1230 Domzale, Slovenia

*To whom correspondence should be addressed. Tel: +1 415 502 1902; Fax: +1 415 502 1901; Email: matija{at}itsa.ucsf.edu

Received October 13, 2005. Revised November 16, 2005. Accepted November 16, 2005.

Transcriptional elongation of most eukaryotic genes by RNA polymerase II requires the kinase activity of the positive transcription elongation factor b (P-TEFb). The catalytically active P-TEFb complex becomes inactive when sequestered into the large complex by the cooperative actions of 7SK snRNA and HEXIM1. In this study, we report that HEXIM1 forms oligomers in cells. This oligomerization is mediated by its predicted coiled-coil region in the C-terminal domain and 7SK snRNA that binds a basic region within the central part of HEXIM1. Alanine-mutagenesis of evolutionary conserved leucines in the coiled-coil region and the digestion of 7SK snRNA by RNase A treatment prevent this oligomerization. Importantly, mutations of the N-terminal part of the coiled-coil region abrogate the ability of HEXIM1 to bind and inhibit P-TEFb. Finally, the formation of HEXIM1 oligomers via the C-terminal part of the coiled-coil or basic regions is critical for the inhibition of transcription. Our results suggest that two independent regions in HEXIM1 form oligomers to incorporate P-TEFb into the large complex and determine the inhibition of transcriptional elongation.


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