Structural basis of AAUAAA polyadenylation signal recognition by the human CPSF complex

Mammalian mRNA biogenesis requires specific recognition of a hexanucleotide AAUAAA motif in the polyadenylation signals (PAS) of precursor mRNA (pre-mRNA) transcripts by the cleavage and polyadenylation specificity factor (CPSF) complex. Here we present a 3.1-Å-resolution cryo-EM structure of a core CPSF module bound to the PAS hexamer motif. The structure reveals the molecular interactions responsible for base-specific recognition, providing a rationale for mechanistic differences between mammalian and yeast 3′ polyadenylation. The cryo-EM structure of the human core CPSF complex, containing CPSF160, WDR33, CPSF30 and Fip1 subunits, bound to its RNA target reveals the mechanism of PAS recognition.