Nucleic Acids Research, Vol 26, Issue 20 4645-4651, Copyright © 1998 by Oxford University Press
P Dhordain, RJ Lin, S Quief, D Lantoine, JP Kerckaert, RM Evans and O Albagli
Recent works demonstrated that some transcriptional repressors recruit
histone deacetylases (HDACs) either through direct interaction, or as a
member of a multisubunit repressing complex containing other components
referred to as corepressors. For instance, the bHLH-Zip transcriptional
repressors MAD/MXI recruit HDACs together with the mSIN3 corepressors,
whereas unliganded nuclear receptors contact another corepressor, SMRT (or
its relative N-CoR), which, in turn, associates with both mSIN3 and HDACs
to form the repressor complex. Recently, we reported that SMRT also
directly associates with LAZ3(BCL-6), a POZ/Zn finger transcriptional
repressor involvedin the pathogenesis of non-Hodgkin lymphomas. However,
whether LAZ3 recruits the HDACs-containing repression complex is currently
unknown. We report here that LAZ3 associates with corepressor mSIN3A both
in vivo and in vitro , and found that a central region, which harbours
autonomous repression activity, is mainly responsible for this interaction.
Conversely, the N- terminal half of mSIN3A is both necessary and sufficient
to bind LAZ3. Moreover, we show that LAZ3 also interacts with an HDAC
(HDAC-1) through its POZ domain in vitro while the immunoprecipitation of
LAZ3 results in the coretention of an endogenous HDAC activity in vivo .
Finally, inhibitors of HDACs significantly reduce the LAZ3-mediated
repression. Taken together, we conclude that LAZ3 recruits a repressing
complex containing SMRT, mSIN3A and a HDAC, and that its full repressing
potential on transcription requires HDACs activity. Our results identify
HDACs as molecular targets of LAZ3 oncogene and further strengthen the
connection between aberrant chromatin acetylation and human cancers.
ARTICLES
The LAZ3(BCL-6) oncoprotein recruits a SMRT/mSIN3A/histone deacetylase containing complex to mediate transcriptional repression
U124 INSERM/IRCL, Place de Verdun, F-59045 Lille cedex, France and Howard Hughes Medical Institute and The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. dhordain@infobiogen.fr
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