The end of the message: multiple protein-RNA interactions define the mRNA polyadenylation site

Abstract

The key RNA sequence elements and protein factors necessary for 3' processing of polyadenylated mRNA precursors are well known. Recent studies, however, have significantly reshaped current models for the protein-RNA interactions involved in poly(A) site recognition, painting a picture more complex than previously envisioned and also providing new insights into regulation of this important step in gene expression. Here we review the recent advances in this area and provide a perspective for future studies.

Keywords: gene expression; mRNA processing; poly(A) site recognition.

Figure 1.

(A) Schematic models showing distinct modules within CPSF. CPSF73, CPSF100, and Symplekin form a module (which we refer to as mCF) that contains the endonuclease activity. mCF may cooperate with different RNA-binding modules, such as mammalian polyadenylation specificity factor (mPSF) (Wdr33, CPSF30, Fip1, and CPSF160), for cleavage/polyadenylation of most mRNAs or with SLBP and U7 snRNP for the cleavage of histone mRNAs. (B, bottom panel) Domain structures of the CPSF subunits involved or implicated in RNA binding. The known or putative RNA-binding regions are marked with red solid or dotted underlines.

Figure 2.

(A) CstF-dependent and potentially CstF-independent PAS recognition. In the CstF-independent model, CstF is shown in a dotted boundary to indicate that CstF may or may not be present in this complex. The scaffolding protein Symplekin plays a role in bridging CPSF–CstF complexes. (B) CFI–RNA interactions. (Top panel) CFI binds to UGUA motifs often found upstream of the AAUAAA hexamer. (Bottom panel) The CFI dimer may bind to two UGUA sequences at different PASs, thus looping out the proximal PASs. (C) The role of Rbbp6 in PAS recognition. The question mark denotes the fact that Rbbp6 may or may not directly interact with upstream AU-rich elements (AREs) or may rely on an unknown factor.

Figure 3.

Context-dependent regulation of PAS recognition. Regulatory factors bound at different locations relative to the core PAS sequence have different effects on PAS recognition by the mRNA 3′ processing factors. Positive effects are indicated by an arrow, and negative effects are indicated by a vertical line.