Control of poly(A) tail length

A mechanistic model for the control of poly(A) tail length: Cleavage and polyadenylation specificity factor (CPSF) binds the polyadenylation signal AAUAAA and recruits poly(A) polymerase (PAP). The first PABPN1 molecule joins the complex once its minimal binding site has been created (∼12 nucleotides). As the tail grows, it is covered by additional PABPN1 molecules. During elongation, folding back of the RNA is necessary to maintain a contact between CPSF and PAP, and this is favored by the formation of a spherical PABPN1 particle on the growing poly(A) tail. In this manner, PAP interacts cooperatively with both CPSF and PABPN1 and synthesizes the entire poly(A) tail in a single processive event. When the poly(A) tail exceeds a critical length of ∼250 adenylate residues, additional PABPN1 molecules can no longer be accommodated in the spherical RNA–protein complex, and the contact between PAP and CPSF is disrupted. Thus, during further elongation of the poly(A) tail, PAP is held in the complex only by PABPN1; elongation becomes poorly processive and, therefore, slow. Note that this model predicts a poorly processive reaction during the addition of the first 12 nucleotides. This is in fact seen in a reconstituted reaction, but not when coupled cleavage and polyadenylation are carried out in crude nuclear extract; presumably, interactions in the cleavage complex are not broken until the poly(A) tail has reached a certain length and maintain the processivity of polyadenylation until PABPN1 has joined the complex. (Reprinted with permission from Ref 39. Copyright 2009 American Society for Biochemistry and Molecular Biology)