A novel domain that recruits the Polycomb Group Polycomb group (PcG) proteins were first discovered for their silencing function of the homeotic (Hox) genes in Drosophila melanogaster. These proteins form transcriptionally repressive complexes that mediate epigenetic modifications of histones. Much is unknown about these complexes, including how they are recruited to specific genes and how H2A ubiquitylation mediates repression. Current speculation is that H2A ubiquitylation either recruits repressive complexes or prevents recruitment of complexes needed for transcription. The importance of these epigenetic modifications is reflected by the observations that misregulation of PcG proteins have been associated with many malignancies. Aberrant expression, mutations and chromosomal translocations of PcG proteins have been observed in a wide variety of cancers. The number of genes encoding PcG proteins in mammals has expanded relative to Drosophila suggesting a greater complexity of function and molecular mechanism. Humans have six orthologs of the Drosophila PcG protein Psc: NSPC1, PCGF3, PCGF5, BMI-1, MEL18, and MBLR, all of which contain a ubiquitin (Ub) fold domain for interaction with other proteins. Binding studies suggest the existence of distinct functional classes of Ub folds within the PcG. Our hypothesis is that the Ub fold domains of Psc orthologs may have evolved to bind different proteins to form distinct repressive complexes. In the BCOR complex, the NSPC1 Ub fold binds BCL6 Co-Repressor (BCOR), which in turn binds F-box and Leucine Rich Repeat 10 (FBXL10), a histone demethylase thus coupling PcG repression with histone demethylation. Mutation of BCOR in humans is responsible for the developmental syndrome OFCD and recent studies have implicated both BCOR and FBXL10 in hematopoietic malignancies. Our preliminary studies have shown that the binding region of BCOR to NSPC1 contains a novel fold, which may provide information as to how these paralogs form distinct repressive complexes. Other data hints that the minimal binding region of FBXL10 on BCOR may overlap with that of NSPC1. The goal is to determine the combined structure of the interacting domains of the NSPC1, BCOR, and FBXL10 triple complex. Solving this structure will be important for elucidating the differences in binding partners that are bound by the ubiquitin fold containing proteins and possibly identifying novel drug targets.

Public Health Relevance

Polycomb Group (PcG) proteins are complexes that repress transcription of a variety of different genes. Deregulation of these proteins is observed in a wide variety of different cancers. Investigating the structure of these proteins is important in understanding their mechanisms of action and understanding their role in the development and progression of cancer.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F08-Q (20))
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Gaillard, Shawn R
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University of Texas Health Science Center San Antonio
Schools of Medicine
San Antonio
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Nanyes, David R; Junco, Sarah E; Taylor, Alexander B et al. (2014) Multiple polymer architectures of human polyhomeotic homolog 3 sterile alpha motif. Proteins 82:2823-30