In higher eukaryotes mRNA 3'-end formation occurs in two ways. For the replication-dependent histone mRNAs 3'-end formation occurs by a cleave-and-trim process. For all other mRNAs 3'-ends are formed by cleavage and polyadenylation as illustrated here.

Cleavage and polyadenylation is directed by a poly(A) signal in the RNA. The core poly(A) signal for vertebrate pre-mRNAs consists of two recognition elements (red) flanking a cleavage-polyadenylation site. Typically, an almost invariant AAUAAA hexamer lies 20-50 nucleotides upstream of a more variable element rich in U or GU residues. Cleavage of the nascent transcript occurs between these two elements and is coupled to the addition of up to 250 adenosines to the 5' cleavage product. Usually mutation (e.g. in green) of the hexamer completely inactivates the poly(A) signal.

In vitro, under non-coupling conditions, cleavage can be mediated by a minimal protein complex that can be separated into five factors. Two of these factors are the cleavage and polyadenylation specificity factor (CPSF) which binds the AAUAAA motif and the cleavage stimulation factor (CstF) which binds the downstream U-rich element. Under coupling conditions, many additional factors are required.

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