Abstract
Polycomb repressive complex 1 (PRC1) is critical for mediating gene repression during development and adult stem cell maintenance. Five CBX proteins, CBX2,4,6,7,8, form mutually exclusive PRC1 complexes and are thought to play a role in the association of PRC1 with chromatin. Specifically, the N-terminal chromodomain (CD) in the CBX proteins is thought to mediate specific targeting to methylated histones. For CBX8, however, the chromodomain has demonstrated weak affinity and specificity for methylated histones in vitro, leaving doubt as to its role in CBX8 chromatin association. Here, we investigate the function of the CBX8 CD in vitro and in vivo. We find that the CD is in fact a major driver of CBX8 chromatin association and determine that this is driven by both histone and previously unrecognized DNA binding activity. We characterize the structural basis of histone and DNA binding and determine how they integrate on multiple levels. Notably, we find that the chromatin environment is critical in determining the ultimate function of the CD in CBX8 association.
Highlights
Two orientations of the structure are shown rotated 180o about the y-axis. d) Residues with significant CSPs upon addition of unmodified NCP plotted onto a cartoon and surface representation of the CD (PDBID 3I91) and colored gold
CSP (Δ ) between the apo and H3K9me3-bound (1:10 ratio, top), DNA and H3K9me3-bound (1:1:10, middle-top), apo and H3K27me3-bound (1:10, middle-bottom) and DNA and H3K27me3-bound (1:1:10, bottom) spectra are plotted against CBX8 residue number
From the crystal structure PDBID 3I91 is diagramed above the Δ plots with the aromatic cage residues labeled
Summary
D) Residues with significant CSPs upon addition of unmodified NCP plotted onto a cartoon and surface representation of the CD (PDBID 3I91) and colored gold.
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