mRNA decay enzymes: Decappers conserved between yeast and mammals

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Abstract
Messenger RNA turnover is a critical determinant of eukaryotic gene expression. The stability of different mRNAs within the same cell can vary by orders of magnitude and thus contribute greatly to differential expression levels. Moreover, the stability of individual mRNAs can be regulated in response to a variety of stimuli, allowing for rapid alterations in gene expression. But how does eukaryotic mRNA turnover work, and how is it controlled? In this issue of PNAS, Wang et al. (1) provide a piece to the puzzle as to how eukaryotic mRNAs are degraded. Early experiments in several eukaryotic systems revealed that the 5′ m7G cap and the 3′ poly(A) tail are critical protective features of mRNAs. Work in the yeast Saccharomyces cerevisiae has uncovered two general mRNA decay pathways that act on these protective ends (Fig. 1; reviewed in ref. 2). These pathways are general in that they appear to degrade most, if not all, normal mRNAs. The first step in both of these pathways is shortening of the poly(A) tail (3–5), which can be catalyzed by one of two different enzymes. The major deadenylase appears to be a large ≈1-mDa complex consisting of one known catalytic subunit, Ccr4p (6–8), a member of the ExoIII/AP endonuclease family (9), and several other proteins, most notably, Pop2, Not1, Not2, Not3, Not4, and Not5 (10). Alternatively, a complex of Pan2p/Pan3p can also function as a cytoplasmic deadenylase (6, 11, 12). Figure 1 Eukaryotic mRNA decay mechanisms and enzymes. Two general mRNA decay pathways. Both pathways are initiated by deadenylation by the Ccr4/Pop2/Not complex or possibly by the alternative deadenylases, Pan2/Pan3 and PARN. Poly(A) tail shortening can lead to either 3′-5′ exonucleolytic digestion by the exosome or decapping by the Dcp1/Dcp2 complex. Decapping is followed by 5′-3′ exonuclease digestion by Xrn1. …