Nucleic Acids Research Advance Access originally published online on February 16, 2008
Nucleic Acids Research 2008 36(7):2219-2229; doi:10.1093/nar/gkn061
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Nucleic Acids Research, 2008, Vol. 36, No. 7 2219-2229
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
LARP7 is a stable component of the 7SK snRNP while P-TEFb, HEXIM1 and hnRNP A1 are reversibly associated
1Molecular and Cellular Biology Program, University of Iowa, Iowa City, Iowa, USA, 2Gene Transcription and Proteomics Laboratory, Institut de recherches cliniques de Montréal, 3Human Retrovirology Laboratory, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada H2W 1R7, 4UMR 8541 CNRS, Ecole Normale Supérieure, 75230 Paris Cedex 05, France and 5Biochemistry Department, University of Iowa, Iowa City, Iowa, USA
*To whom correspondence should be addressed. Tel: +1 319 335 7910; Fax: +1 319 384 4770; Email: david-price{at}uiowa.edu
Received December 17, 2007. Revised January 30, 2008. Accepted January 30, 2008.
Regulation of the elongation phase of RNA polymerase II transcription by P-TEFb is a critical control point for gene expression. The activity of P-TEFb is regulated, in part, by reversible association with one of two HEXIMs and the 7SK snRNP. A recent proteomics survey revealed that P-TEFb and the HEXIMs are tightly connected to two previously-uncharacterized proteins, the methyphosphate capping enzyme, MEPCE, and a La-related protein, LARP7. Glycerol gradient sedimentation analysis of lysates from cells treated with P-TEFb inhibitors, suggested that the 7SK snRNP reorganized such that LARP7 and 7SK remained associated after P-TEFb and HEXIM1 were released. Immunodepletion of LARP7 also depleted most of the 7SK regardless of the presence of P-TEFb, HEXIM or hnRNP A1 in the complex. Small interfering RNA knockdown of LARP7 in human cells decreased the steady-state level of 7SK, led to an initial increase in free P-TEFb and increased Tat transactivation of the HIV-1 LTR. Knockdown of LARP7 or 7SK ultimately caused a decrease in total P-TEFb protein levels. Our studies have identified LARP7 as a 7SK-binding protein and suggest that free P-TEFb levels are determined by a balance between release from the large form and reduction of total P-TEFb.
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