The proto-oncogene BCL-6 encodes a transcriptional repressor that is essential for normal lymphocyte development and regulation of inflammation. Chromosomal translocations that prevent the normal down regulation of BCL-6 during B cell development have been implicated in the generation of two subtypes of non-Hodgkins lymphoma. BCL-6 normally represses the transcription of genes involved in B cell activation, B cell differentiation, inflammation, and cell cycle control, and the inappropriate repression of some of these genes is likely to contribute to lymphoma. The objective of the proposed research is to understand the molecular mechanisms of BCL-6 repression. BCL-6 contains a protein-protein interaction motif called the POZ domain, which serves as the major repression domain of the protein. We have found that the POZ domain of BCL-6 interacts with the corepressors N-CoR and SMRT, as well as with a novel corepressor we called BCoR. Strikingly, BCoR interacts selectively with the BCL-6 POZ domain, suggesting that it may play a particularly important role in BCL-6 repression. In the work proposed below we will study the role of these corepressors in BCL-6 repression and perform a biochemical analysis of the BCoR complex and a genetic analysis of BCoR function. We have three main aims. First, we will determine whether BCL.6 recruits particular corepressors to particular target gene promoters, and if so, under what conditions. Second, we will biochemically purify and identify components of the BCoR complex, and functionally analyze a small number of these components. Third, we will make a conditional mouse mutant of BCoR, and study the effects of global or cell type-specific deletion of the gene. This work seeks to elucidate how BCL-6 regulates target genes normally and how inappropriate BCL-6 activity contributes to B cell lymphoma.
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