Structural Basis of RACK7 PHD Domain to Read a Pediatric Glioblastoma‐Associated Histone Mutation H3.3G34R

Abstract

Main observation and conclusionHistone point mutations, including missense mutations on histone H3 at positions 27 (K27M), 34 (G34R/V, G34W, G34L) and 36 (K36M), were identified as potential cancer driver mutations. H3.3G34R/V mutations account for pediatric glioblastomas (GBM). RACK7 (also known as ZMYND8, PRKCBP1) was recently reported to specifically bind H3.3G34R through its PHD (plant homedomain) domain (PHDRACK7) in vitro and in H3.3G34R pediatric glioblastoma cells, playing key roles in H3.3G34R‐mediated gene transcription. Herein, we provided both biochemical and NMR structural evidences that PHDRACK7 recognized histone H3.3G34R mutant via a mechanism distinct from all other reported PHD domains. Except the reported residue D104, two new sites D108 and L121 of PHDRACK7 were found necessary for the interactions between PHDRACK7 and histone H3.3G34R peptide. Our results provided a potential molecular basis for pediatric GBM driven by the H3.3G34R mutation.