Polyadenylation: alternative lifestyles of the A-rich (and famous?).

Alternative polyadenylation has a major function in gene expression and is often mediated through signals that lack canonical signatures. In this issue, Nunes et al (2010) uncover a new upstream A-rich sequence element that in conjunction with a strong U/GU-rich downstream element may be responsible for up to a third of polyadenylation events in mammalian cells that are not mediated by a canonical AAUAAA hexamer. In the not too distant past, the process of mRNA 30 end formation (aka polyadenylation) was largely considered a default event along the pathway of gene expression. It is now abundantly clear that polyadenylation is not only a fundamental step in mRNA biogenesis but is also highly regulated and networked with other aspects of gene expression. Interestingly, recent evidence indicates that the choice of polyadenylation site in many mRNAs changes in response to cell growth, developmental cues or oncogene activation (Ji and Tian, 2009; Mayr and Bartel, 2009). The resultant shortening of an mRNA’s 30 untranslated region can remove a variety of regulatory elements, including miRNA target sites, and thereby dramatically alter gene expression patterns. Thus, how these alternative polyadenylation sites are selected in the B50% of genes that possess them has emerged as a key question in the gene expression arena. The textbook definition of a mammalian polyadenylation signal is an upstream AAUAAA hexamer plus a less conserved U-rich or GU-rich downstream element. Database analyses, however, show that up to 30% of polyadenylation events do not seem to involve an AAUAAA hexamer (or its close relative AUUAAA) and B50% do not possess either core element. Curiously, many of these ‘non-canonical’ signals lie significantly 50 of the default polyadenylation signal in the 30 untranslated region of a pre-mRNA, making them prime targets for regulation and alternative polyadenylation events. Thus, to elucidate mechanisms of regulated alternative 30 end processing, we need to understand how non-canonical polyadenylation events are carried out. One fundamental aspect of this is to determine the nucleic acid elements or code(s) that mediate non-canonical polyadenylation events. In studying 30 end formation of the melanocortin 4 receptor gene, Nunes et al (2010) in this issue of The EMBO Journal have uncovered what seems to be a major new class of non-canonical mammalian polyadenylation signal. This new ‘A-rich’ class of poly(A) signals is comprised of a critical U/GU-rich downstream core element and an upstream A tract (Figure 1). Thus, it completely lacks an AAUAAA hexamer and is reminiscent of 30 end processing signals in plants and yeast. Furthermore, bioinformatic analysis suggests that A-rich poly(A) signals may account for up to a third of noncanonical 30 end processing events in mammalian cells. Finally, as changing AAUAAA to AAAAAA in the context of a standard poly(A) signal significantly reduces processing efficiency, the ability of an upstream A tract to function in 30 end processing is considerably context dependent. Thus, the bottom line is that it seems we have a new upstream core polyadenylation element and class of poly(A) signals in town. These observations are of significant interest for three main reasons. First, the discovery of A-rich core upstream polyadenylation elements obviously provides considerable insight into the cis-acting sequences involved in alternative polyadenylation events that have a major, only recently appreciated function in determining the landscape of the transcriptome. The A-rich element is the first major new upstream core metazoan polyadenylation element to be identified since the Gilmartin laboratory uncovered a role for UGUAN sequences in the 30 end processing of select mRNAs (Venkataraman et al, 2005). Second, the study highlights the significant function played by the downstream