Regulation of mRNA decapping

mRNA 5′ to 3′ decay pathway. Following deadenylation, the 5′ cap of an mRNA is cleaved by the Dcp2 decapping enzyme and the resulting 5′‐end monophosphorylated mRNA is degraded by the Xrn1 exoribonuclease. Known positive (indicated by the plus sign) and negative (indicated by the minus sign) regulators of Dcp2 are listed.

Models demonstrating activation of Dcp2 decapping by cis‐elements. (a) Activation of Dcp2 decapping by an AU‐rich element (ARE) element is shown. TTP, key component in ARE‐mediated decay, interacts with the decapping complex and promotes decapping of the ARE‐containing mRNA. (b) Activation of Dcp2 decapping by a 3′ end U‐tract is represented. The U‐tract at the 3′ terminus of an mRNA is recognized by the Lsm1–7 complex to recruit a decapping complex. (c) Activation of Dcp2 decapping by a 5′ end stem‐loop structure. mRNAs containing a stem‐loop structure [Dcp2 binding and decapping element (DBDE)] within the first 10 nucleotides at the 5′ end can more efficiently recruit the Dcp2 protein to stimulate decapping.

Model of DcpS decapping cycle. The ligand‐free DcpS dimer shown at the top exhibits a symmetric open conformation with two binding sites for cap structure. With high substrate concentrations (middle), both cap‐binding sites could be occupied as shown. A conformational change occurs to close the N terminus on one of the substrates to create a simultaneous closed and open conformation. Following substrate hydrolysis at the closed site, a conformational change occurs to release the decapping products and the site can be occupied by another substrate to start a new catalytic cycle. Under low substrate concentration, only one of the sites would be expected to be occupied by cap structure. The N terminus at a cap bound site closes for substrate hydrolysis followed by release of the m⁷Gp and ppN decapping products to complete a catalytic cycle. (See Liu et al.30 for a more thorough kinetic description).

Schematic and structural representation of the DcpS decapping protein. The human DcpS protein is schematically represented at the top with the Histidine Triad (HIT) fold and HIT motif regions as described in the text denoted. Crystal structure of the human DcpS homodimer bound to two m⁷GpppG cap structures generated by PyMOL from PDB#1ST0 is shown on the bottom. The two monomers of DcpS are shown in cyan and green, respectively. One monomer (cyan) forms the closed active conformation while the second monomer (green) forms the open inactive conformation. The m⁷GpppG cap structures are represented in red.

Schematic and structural representation of the Dcp2 decapping protein. The human Dcp2 protein is schematically represented at the top with the evolutionarily conserved domains as described in the text noted. Crystal structure of the N‐terminal fragment of Schizosaccharomyces pombe Dcp2 (residues 1–266) generated by PyMOL from PDB#2A6T, is shown on the bottom. Conserved regions are highlighted in the same color scheme as the schematic representation above.

mRNA 3′ to 5′ decay pathway. Following removal of the poly(A) tail, the mRNA can be degraded from the 3′ end by the exosome complex. The resulting cap structure of capped oligonucleotides less than 10 bases long is hydrolyzed by the DcpS scavenger decapping enzyme. Several cellular processes that can be influenced by DcpS are indicated. DcpS is a potential negatively modulator of SMN2 expression16 and it positively regulates 5′ to 3′ exonucleolytic degradation (at least in yeast17) and cap‐proximal pre‐mRNA splicing.18.