DDX46

DEAD-box helicase 46 (DDX46), alias p72 or human PRP5 ortholog, is an ATP-dependent RNA helicase central to pre-mRNA splicing. It drives the transition from spliceosomal complex E to A by remodeling RNA-RNA interactions between U2 snRNP and the pre-mRNA branch point sequence (BPS). Using ATP hydrolysis, DDX46 stabilizes U2 snRNP’s BPS binding, a prerequisite for functional spliceosome assembly and accurate intron excision.
Dysregulated DDX46 contributes to multiple diseases: de novo mutations cause autosomal dominant intellectual disability and developmental delay, while overexpression promotes hepatocellular carcinoma progression via aberrant splicing. Direct therapeutic targeting of DDX46 remains preclinical, with research focusing on small molecules modulating its helicase activity to correct splicing defects or inhibit cancer-associated dysregulation.