Structures and function of PHD fingers of ING tumor suppressors

The PHD (plant homeodomain) finger is found in many chromatin associated proteins however its function remains unclear. We found that a subset of PHD fingers targets tri‐methylated histone H3 (H3K4me3) tail and represents a novel family of effector proteins that recognize this epigenetic mark1,2. We have determined structures of the PHD fingers of ING (inhibitor of growth) tumor suppressors in complex with a histone H3K4me3 peptide and characterized their specificity toward post‐translationally modified histone tails. The H3K4me3 peptide is bound in an extended conformation in a deep and extensive binding site consisting of elements that are conserved among other PHD fingers. The trimethylammonium group of Lys 4 is recognized by aromatic residues of the domain, whereas the intermolecular hydrogen‐bonding and complementary surface interactions, involving five peptide residues, account for the PHD finger's high specificity and affinity. Substitution of the binding site residues disrupts H3K4me3 interaction in vitro and impairs the ability of ING to induce apoptosis, suggesting a novel tumor suppressive mechanism. Strong binding of yeast YNG PHD fingers indicates that the recognition of the H3K4me3 histone code is a general function of this protein family. Supported by the NIH and AHA (CA113472, GM071424 and 0555561Z to T.G.K.).