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Critical Residues within the BTB Domain of PLZF and Bcl-6 Modulate Interaction with Corepressors

Division of Hematology,¹ The Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029,² Division of Molecular and Structural Biology, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2M9,³ Department of Genetics, Cell Biology, and Development, Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455⁴

Received 24 September 2001/ Returned for modification 16 November 2001/ Accepted 10 December 2001

The PLZF (promyelocytic leukemia zinc finger) transcriptional repressor, when fused to retinoic acid receptor alpha (RAR), causes a refractory form of acute promyelocytic leukemia. The highly conserved N-terminal BTB (bric a brac, tramtrack, broad complex)/POZ domain of PLZF plays a critical role in this disease, since it is required for transcriptional repression by the PLZF-RAR fusion protein. The crystal structure of the PLZF BTB domain revealed an obligate homodimer with a highly conserved charged pocket formed by apposition of the two monomers. An extensive structure-function analysis showed that the charged pocket motif plays a major role in transcriptional repression by PLZF. We found that mutations of the BTB domain that neutralize key charged pocket residues did not disrupt dimerization, yet abrogated the ability of PLZF to repress transcription and led to the loss of interaction with N-CoR, SMRT, and histone deacetylases (HDACs). We extended these studies to the Bcl-6 protein, which is linked to the pathogenesis of non-Hodgkin's lymphomas. In this case, neutralizing the charged pocket also resulted in loss of repression and corepressor binding. Experiments with purified protein showed that corepressor-BTB interactions were direct. A comparison of the PLZF, Bcl-6, and the FAZF (Fanconi anemia zinc finger)/ROG protein shows that variations in the BTB pocket result in differential affinity for corepressors, which predicts the potency of transcriptional repression. Thus, the BTB pocket represents a molecular structure involved in recruitment of transcriptional repression complexes to target promoters.

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