Abstract C28: Binding to BCOR defines a subfamily of Psc ortholog mediated polycomb group complexes

Abstract

Abstract NSPC1 is a Polycomb group (PcG) protein that functions within a multiprotein complex containing BCOR (BCL6 Co-Repressor), a protein which has been shown to drive formation of diffuse large B cell leukemia. NSPC1 is one of six human homologs (BMI1, MEL18, NSPC1, MBLR, PCGF3 and PCGF5) of the Drosophila Polycomb group (PcG) protein Psc. While BMI1 and MEL18 can bind directly to another PcG protein called Polyhomeotic (PH), multi-protein complexes involving MBLR and NSPC1 are absent of PH and no function has yet to be assigned to PCGF3 or PCGF5. We show that the ubiquitin (Ub) fold of NSPC1 and PCGF3 does not bind PH, but instead directly interacts with a previously unrecognized 115 residue region within BCOR while the Ub folds of BMI1 and MEL18 bind only PH. Preliminary structural studies using nuclear magnetic resonance and analytical ultracentrifugation indicate that this region of BCOR can independently fold and possesses a novel structure thereby identifying this domain as a unique PcG recruiting module. Thus, we propose the presence of at least two distinct functional classes of Psc orthologs: Class I, (BMI1 and MEL18) that binds PH and Class II (PCGF3, NSPC1 and likely PCGF5) which bind BCOR. The existence of different classes of Psc homologs demonstrates the evolution of the PcG in order to diversify its silencing function. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C28.