Polycomb Group and SCF Ubiquitin Ligases Are Found in a Novel BCOR Complex That Is Recruited to BCL6 Targets

Abstract

The corepressor BCOR potentiates transcriptional repression by the proto-oncoprotein BCL6 and suppresses the transcriptional activity of a common mixed-lineage leukemia fusion partner, AF9. Mutations in human BCOR cause male lethal, X-linked oculofaciocardiodental syndrome. We identified a BCOR complex containing Polycomb group (PcG) and Skp-Cullin-F-box subcomplexes. The PcG proteins include RING1, RYBP, NSPC1, a Posterior Sex Combs homolog, and RNF2, an E3 ligase for the mono-ubiquitylation of H2A. BCOR complex components and mono-ubiquitylated H2A localize to BCL6 targets, indicating that the BCOR complex employs PcG proteins to expand the repertoire of enzymatic activities that can be recruited by BCL6. This also suggests that BCL6 can target PcG proteins to DNA. In addition, the BCOR complex contains components of a second ubiquitin E3 ligase, namely, SKP1 and FBXL10 (JHDM1B). We show that BCOR coimmunoprecipitates isoforms of FBXL10 which contain a JmjC domain that recently has been determined to have histone H3K36 demethylase activity. The recruitment of two distinct classes of E3 ubiquitin ligases and a histone demethylase by BCOR suggests that BCOR uses a unique combination of epigenetic modifications to direct gene silencing.

Supplemental material for this article may be found at http://mcb.asm.org/.

We thank Haruhiko Koseki (Riken, Japan) for RNF2 antibody, Khanh Huynh and Jeannie Lee (Harvard University) for trophoblastic stem cells, Jose Polo and Ari Melnick (Albert Einstein College of Medicine, New York) for sharing BCL6 target primer sequences, and Carrie Ketel and Jeff Simon (University of Minnesota) for oligonucleosome substrate. We thank colleagues for helpful comments.

This work was supported by a grant to V.J.B. from the NCI (RO1-CA071540). M.D.G. was supported by training grants from the NCI and the NIDCR.