mRNA degradation

All organisms require a reliable mechanism to turn genes on and off. This regulation of gene expression underlies cellular processes ranging from the response to environmental signals to the development of multi-cellular organisms and cell-cell communication. Understandably, the cell tightly controls gene expression at every step from DNA to protein. Recent work has given new insights into these control mechanisms and revealed dedicated pathways that target mRNA for degradation, thereby efficiently turning genes off.

After export to the cytoplasm, mRNA is protected from degradation by a 5’ cap structure and a 3’ poly adenine tail. In the deadenylation dependent mRNA decay pathway, the polyA tail is gradually shortened by exonucleases. This ultimately attracts the degradation machinery that rapidly degrades the mRNA in both in the 5’ to 3’ direction and in the 3’ to 5’ direction. Additional mechanisms, including the nonsense mediated decay pathway, bypass the need for deadenylation and can remove the mRNA from the transcriptional pool independently. Interestingly, the same enzymes are responsible for the actual degradation of the mRNA independent of the pathway taken (see figure).

mRNA degradation
Figure 1: Simplified mechanism of mRNA decay. Dotted arrows indicate (indirect) interactions. Details of the pathways vary between different eukaryotes. PAB: poly-A binding protein.

Crystal structures for some of the complexes that play a role in mRNA decay have been solved, including the DCP1:DCP2 decapping complex, the DCPS scavenger decapping complex and the multi-component exosome complex. Our understanding of enzyme function is, however, limited to a static 3 dimensional fold of one of the many conformations that these proteins can adopt. To fully understand how molecular motions lead to catalytic activity a complete picture of the protein dynamics is required. In addition, the catalytic activity of these enzymes must be tightly regulated to prevent premature degradation of mRNA and to ensure maximum activity as soon as an mRNA has been identified as a substrate. As such, intermolecular interactions that modulate catalytic activity, e.g. by restricting molecular motions are of foremost interest.

Figure 2: Examples of protein decapping enzymes that can adept different conformations. Left: the Dcp1:Dcp2 complex (She et. al. Mol Cell 2008, She et. al. Nat Struct Mol Biol. 2006; 2QKM, 2A6T). Right: DcpS in the open and closed state (Gu et. al. Mol Cell 2004; 1XMM, 1XML)