The LAZ3͞BCL6 (lymphoma-associated zinc finger 3͞B cell lymphomas 6) gene frequently is altered in non-Hodgkin lymphomas. It encodes a sequence-specific DNA binding transcriptional repressor that contains a conserved N-terminal domain, termed BTB͞POZ (bric-à-brac tramtrack broad complex͞pox viruses and zinc fingers). Using a yeast two-hybrid screen, we show here that the LAZ3͞BCL6 BTB͞ POZ domain interacts with the SMRT (silencing mediator of retinoid and thyroid receptor) protein. SMRT originally was identified as a corepressor of unliganded retinoic acid and thyroid receptors and forms a repressive complex with a mammalian homolog of the yeast transcriptional repressor SIN3 and the HDAC-1 histone deacetylase. Protein binding assays demonstrate that the LAZ3͞BCL6 BTB͞POZ domain directly interacts with SMRT in vitro. Furthermore, DNAbound LAZ3͞BCL6 recruits SMRT in vivo, and both overexpressed proteins completely colocalize in nuclear dots. Finally, overexpression of SMRT enhances the LAZ3͞BCL6-mediated repression. These results define SMRT as a corepressor of LAZ3͞BCL6 and suggest that LAZ3͞BCL6 and nuclear hormone receptors repress transcription through shared mechanisms involving SMRT recruitment and histone deacetylation.The LAZ3͞BCL6 (lymphoma-associated zinc finger 3͞B cell lymphomas 6) gene has been cloned by virtue of its frequent structural alteration in both diffuse large cell and follicular lymphomas (1-3). These alterations include translocations, small deletions, and point mutations. Most of them have been found in a genomic region, called the major translocation cluster, containing the first noncoding exon and the first downstream intron of the LAZ3͞BCL6 locus (4-8). It usually is proposed that such structural alterations lead to the deregulation of LAZ3͞BCL6 expression and, hence, contribute to lymphomagenesis (4, 7). The normal LAZ3͞BCL6 expression pattern suggests its implication in B cell differentiation and in the control of T cell-dependent immune response (9). Recent genetic experiments in mouse abrogating LAZ3͞BCL6 expression or leading to the expression of an inactive deleted version of this protein substantiate this hypothesis. Indeed, mice deficient for LAZ3͞BCL6 activity are devoid of germinal centers, present a Th2-type inflammatory disease and a defect in T cell-dependent antibody response (10, 11). Taken together, these results suggest that LAZ3͞BCL6-associated lymphomas may occur as a consequence of a deregulated LAZ3͞ BCL6 expression.The LAZ3͞BCL6 gene encodes a sequence-specific transcriptional repressor that harbors six C-terminal C2H2 krüp-pel-like zinc fingers. These zinc fingers are responsible for the sequence-specific DNA binding of the protein. At its Nterminal part, LAZ3͞BCL6 also contains an Ϸ130-aa conserved domain termed the BTB͞POZ (bric-à-brac tramtrack broad complex͞pox viruses and zinc fingers) domain (12,13). This domain has been identified in Ϸ40 proteins found in Metazoans and poxviruses (13). In LAZ3͞BCL6, the BTB͞ POZ domain mediates self-interaction an...

We have shown previously that chromosomal translocations involving chromosome 3q27 and immunoglobulin gene regions are the third most common specific translocations in non-Hodgkin's lymphoma (NHL). We now report the isolation of a gene that is disrupted in two cases by t(3;14) and t(3;4) translocations. The gene (LAZ3) encodes a 79 kDa protein containing six zinc-finger motifs and sharing amino-terminal homology with several transcription factors including the Drosophila tramtrack and Broad-complex genes, both of which are developmental transcription regulators. LAZ3 is transcribed as a 3.8 kb message predominantly in normal adult skeletal muscle and in several NHL carrying 3q27 chromosomal defects. We suggest that it may act as a transcription regulator and play an important role in lymphomagenesis.

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.