Figure 2.

Different models of how loss of SLBP monoubiquitination by CRL4^WDR23 may lower histone mRNA processing activity. Given that CRL4^WDR23 targets the RBD of SLBP, it is conceivable that ubiquitination positively influences SL binding by lowering the dissociation rate of SLBP for the SL (i.). Although SLBP has an intrinsic affinity for the SL, reinforcement of this interaction might stabilize SLBP-mRNA association until the histone transcripts are translated in the cytoplasm. Alternatively, exposed ubiquitin moieties on SLBP might create binding sites for the components of the endonucleotytic machinery, in particular the CCC (ii.) and/or U7 snRNP (iii.). In each case, poor recruitment of one or both complexes would cause a severe block to mRNA cleavage. It is also conceivable that the lack of SLBP monoubiquitination leaves the initial assembly of the endonucleolytic machinery unperturbed, but has effects on its processivity. In cells, the cleavage of histone pre-mRNA is greatly enhanced by the recruitment of the spliceosomal U2 snRNP complex upstream of the SL. Ubiquitinated SLBP might thus contribute to this step, either by exposing an additional binding site for U2 snRNP or by together configuring an overall architecture that favors CCC/U7 snRNP-dependent histone mRNA cleavage (iv.). Lastly, the U2 snRNP complex contains the DEAH box helicase hPrp43, and its RNA helicase activity was previously suggested to facilitate the disassembly of the cleavage machinery before the export of the mature histone transcript. Ubiquitinated SLBP might block the catalytic activity of hPrp43 to allow completion of the cleavage reaction. Hence, a defect in SLBP ubiquitination would lead to constitutive hPrp43 helicase activity and the premature release of individual subcomplexes from the mRNA (v.).