In addition to alternative splicing, which occurs in one tissue or another for some 95 percent of human genes, alternative polyadenylation occurs for some 50 percent of human mRNAs. Alternative polyadenylation results from the use of two or more alternative polyadenylation signals in different cell types. In some cases, this appears to be due to different concentrations of cleavage/polyadenylation factors in different cell types coupled with alternative poly(A) signals that have higher or lower affinity for the CStF complex that binds the downstream G/U-rich portion of the cleavage/polyadenylation signal (see Figure 10-15). In these cases, when the concentration of CStF is low, only the highest-affinity polyadenylation signals are used. But in alternative cell types where the CStF concentration is higher, an upstream low-affinity site is used preferentially because once the pre-mRNA is cleaved, the downstream site cannot be used. In other cases, sequence-specific RNA-binding proteins may block or enhance binding of the cleavage/polyadenylation factors, as in the case of splicing repressors and activators.

When multiple mRNAs expressed from the same gene use alternative polyadenylation sites, additional miRNA-binding sites may be located in the mRNA with the longer 3′ exon. As a consequence, mRNAs with the same protein-coding sequence may be regulated differently in different cell types depending on the length of the 3′ UTR and the miRNAs expressed in those cells. Consequently, alternative polyadenylation can regulate the translation of mRNAs encoding the same protein as a consequence of miRNA control of translation and mRNA stability.

Alternative sites of polyadenylation can also be coupled to alternative splicing of the final exon in an mRNA. As a consequence, protein isoforms can be expressed that have different C-terminal amino acid sequences. This type of variation is observed in the expression of alternative immunoglobulin molecules during B-lymphocyte development (see Figure 23-19). Initially, an immunoglobulin antibody is produced with a transmembrane domain, which anchors the antibody in the plasma membrane, and a cytoplasmic domain, which signals when the antigen-binding extracellular domain encounters antigen—the molecule bound by an antibody. When antigen is bound, processing of the pre-mRNA is modified so that an alternative 3′ exon is included in the mRNA. The antibody molecules translated from this alternatively processed mRNA lack the transmembrane domain, and as a consequence, they are secreted into the extracellular space, where they can neutralize pathogens (see Chapters 14 and 23).