New ways to meet your (3′) end—oligouridylation as a step on the path to destruction

Abstract

Messenger RNA degradation is a vital contributor to the control of gene expression that generally involves removal of a poly(A) tail in both prokaryotes and eukaryotes. In a thought-provoking study in this issue of Genes & Development, Mullen and Marzluff (2008) present data supporting a novel mechanism of mRNA decay. They discovered that histone mRNAs, which are unique in that they are never polyadenylated in mammalian cells, degrade by a cell cycle-regulated mechanism that involves addition of a short oligo(U) tail at the 3 end. Interestingly, this oligo(U) tract is recognized by the Lsm1–7 complex, which then appears to feed the transcript into the standard mRNA decay pathways. These findings are exciting because they invoke parallels with prokaryotic mRNA decay, which requires polyadenylation immediately prior to degradation and involves an Lsm homolog, Hfq. Moreover, recent studies have identified other oligouridylated RNAs and several poly(U) polymerases, implying that this may be a more widespread mechanism for turnover of RNA. Messenger RNAs in both prokaryotes and eukaryotes have an interesting problem in that they need to be resistant to decay to be translated but must eventually undergo degradation to allow appropriate regulation of gene expression. At first glance, it appears that these two kingdoms have developed opposite solutions to the problem; in bacteria, polyadenylation induces decay, whereas in eukaryotic cells a poly(A) tail protects the transcript from nucleases, and its removal is the first step in degradation (Dreyfus and Regnier 2002; Edmonds 2002). However, a closer look reveals that a poly(A) tail, through its lack of structure, serves as a primer for decay in both eukaryotes and prokaryotes. The poly(A) tail simply has acquired additional roles in eukaryotic cells. Polyadenylation essentially creates an ssRNA-binding platform at the 3 end of RNAs in order to initiate decay. Results described below indicate that this ssRNA platform can be in the form of either oligo(U) or oligo(A). While the addition of these two homopolymeric tails may accomplish the same endpoint (recruitment of degradative enzymes), they may not be totally interchangeable as each can be regulated differently at the level of synthesis, recruit different regulatory poly(U)- or poly(A)-binding factors, or attract different degradative enzymes to the transcript. This strategy for initiating decay via 3 unstructured extensions may have favored the evolution of the 3 end of RNAs to focus on transcript function rather than on maintaining sequences/ structures that allow for eventual decay of the transcript. It also creates a ready means for the cell to degrade any unwanted transcripts without regard to sequence or structure. In this perspective, we first describe parallels between the role of the poly(A) tail, poly(A) polymerase (PAP), and poly(A) removal in initiating mRNA degradation in prokaryotic and eukaryotic cells. Next we discuss the functions of noncanonical poly(A)/(U) polymerases in mRNA metabolism. We then go on to describe how a newly discovered 3 modification—oligouridylation— may achieve some of the same outcomes. Multiple ways to add and remove poly(A)