Figure 1.

The CRL4^WDR23 ligase activates histone mRNA processing by monoubiquitinating SLBP. (A) Schematic illustration of the nuclear histone mRNA processing pathway. SLBP binds the stem loop (SL) structure on the nascent transcript. Binding of SLBP to the hairpin is required for the subsequent recruitment of the ternary Core Cleavage Complex (CCC), which is composed of the scaffolding protein Symplekin and the endonucleases CPSF100/CPSF73. Together with the U7 snRNP complex, which basepairs with the Histone Downstream Element (HDE) and connects to SLBP via the Zn finger protein ZFP100, the CCC forms the heart of the histone pre-mRNA processing machinery. The endonucleolytic activity is further increased by additional co-factors, driving maturation of histone transcripts and subsequent SLBP-dependent export into the cytoplasm. The CRL4^WDR23 E3 ligase monoubiquitinates SLBP within its RNA binding domain (RBD), and this regulation is critical for the efficiency of the histone mRNA cleavage process but not for nuclear export. (B) Downregulation of the CRL4 adaptor protein WDR23 by siRNA causes a drop in canonical histone levels due to a defect in histone transcript maturation. Extracts from U2OS cells treated with control or WDR23 siRNA were analyzed by SDS-PAGE. Total protein levels were visualized by Coomassie staining.