Plant homeodomain (PHD) fingers are structurally conserved zinc fingers that selectively bind unmodified or methylated at lysine 4 histone H3 tails. This binding stabilizes transcription factors and chromatin-modifying proteins at specific genomic sites, which is required for vital cellular processes, including gene expression and DNA repair. Several PHD fingers have recently been shown to recognize other regions of H3 or histone H4. In this review, we detail molecular mechanisms and structural features of the non-canonical histone recognition, discuss biological implications of the atypical interactions, highlight therapeutic potential of PHD fingers, and compare inhibition strategies.

PHD

histone

binding

chromatin

inhibitor

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