Chromatin Recognition Protein Modules: The PHD Finger

Abstract

The structure of chromatin controls the accessibility to deoxyribonucleic acid (DNA) information. Posttranslational modifications (PTMs) of histones modify the architecture of chromatin and provide docking platforms for proteins that control many DNA‐templated processes. The plant homeodomain (PHD) fingers are small protein domains found in nuclear factors that interact with chromatin. Recent studies have characterised two classes among the PHD fingers, which specifically bind to either unmodified or trimethylated K4 histone H3. A number of PHD finger structures in complex with histone peptides reveal the recognition mechanisms. The combination of multiple histone PTMs, the cooperation between different PHD fingers or between PHD fingers and other histone recognition proteins illustrate the plurality and versatility of this protein module. Mutations or translocations in PHD fingers that affect their interaction with histones have been related to immunological diseases, cancer or mental retardation. Key Concepts: Histone modifications form part of the chromatin control of DNA‐templated processes. PHD fingers are small nuclear protein domains that bind two zinc ions in an interlaced topology. Several PHD fingers specifically recognise the di‐ and trimethylated K4 histone H3 tail, and others bind specifically to unmethylated K4 histone H3. Aromatic cages are cavities formed by the side chains of 2–4 aromatic residues used by PHD fingers and by other protein modules for binding to methylated lysines. Alterations of the histone recognition by PHD fingers are related to immunological diseases, cancer and mental retardation.

The PHD Finger of Human UHRF1 Reveals a New Subgroup of Unmethylated Histone H3 Tail Readers

“…In the past years, the PHD finger has emerged as a versatile protein module for the recognition of the histone H3 tail [27] . In this work we show that the PHD finger of human UHRF1 represents a new mode of histone H3 recognition that requires the appendage of an additional zinc finger, relies mainly on the recognition of H3R2, and shows preference for unmethylated H3K4, although it can accommodate H3K4me3 without compromising the complex formation.…”

Extended Multitarget Pharmacology of Anticancer Drugs

“…The cross-class targeting by a single therapeutic is also expected, because receptors and enzymes for the same substrate may differ by backbone topology, yet contain similar binding sites 34 . In addition, some protein targets contain multiple small-molecule binding sites, which may allow chemically diverse drugs to bind [35][36][37] . For example, it has been shown that protein kinase inhibitors such as, imatinib and nilotinib, are also able to target smoothened receptor of the Hedgehog pathway; celecoxib targets prostaglandin G/H synthase 2, carbonic anhydrases, and several nuclear receptors 38,39 .…”