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Control of poly(A) tail length

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Abstract Poly(A) tails have long been known as stable 3′ modifications of eukaryotic mRNAs, added during nuclear pre‐mRNA processing. It is now appreciated that this modification is much more diverse: A whole new family of poly(A) polymerases has been discovered, and poly(A) tails occur as transient destabilizing additions to a wide range of different RNA substrates. We review the field from the perspective of poly(A) tail length. Length control is important because (1) poly(A) tail shortening from a defined starting point acts as a timer of mRNA stability, (2) changes in poly(A) tail length are used for the purpose of translational regulation, and (3) length may be the key feature distinguishing between the stabilizing poly(A) tails of mRNAs and the destabilizing oligo(A) tails of different unstable RNAs. The mechanism of length control during nuclear processing of pre‐mRNAs is relatively well understood and is based on the changes in the processivity of poly(A) polymerase induced by two RNA‐binding proteins. Developmentally regulated poly(A) tail extension also generates defined tails; however, although many of the proteins responsible are known, the reaction is not understood mechanistically. Finally, destabilizing oligoadenylation does not appear to have inherent length control. Rather, average tail length results from the balance between polyadenylation and deadenylation. WIREs RNA 2011 2 348–361 DOI: 10.1002/wrna.56 This article is categorized under: RNA Processing > 3' End Processing RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms

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)

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RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Processing > 3′ End Processing

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