Non-redundant roles for the human mRNA decapping cofactor paralogs DCP1a and DCP1b

Eukaryotic gene expression is regulated at both the transcriptional and post-transcriptional levels, with disruption of regulation contributing significantly to human diseases. In particular, the 5 m7G mRNA cap is the central node in post-transcriptional regulation, participating in both mRNA stabilization and translation efficiency. DCP1a and DCP1b are paralogous cofactor proteins of the major mRNA cap hydrolase DCP2. As lower eukaryotes have a single DCP1 cofactor, the functional advantages gained by this evolutionary divergence remain unclear. Here we report the first functional dissection of DCP1a and DCP1b, demonstrating that DCP1a and DCP1b are distinct, non-redundant cofactors of the decapping enzyme DCP2, with unique roles in decapping complex integrity and specificity. Specifically, DCP1a is essential for decapping complex assembly and for interactions between the decapping complex and mRNA cap binding proteins. In contrast, DCP1b is essential for decapping complex interactions with the translational machinery. Additionally, DCP1a and DCP1b impact the turnover of distinct mRNAs. The observation that different ontological groups of mRNA molecules are regulated by DCP1a and DCP1b, along with their non-redundant roles in decapping complex integrity, provides the first evidence that these highly similar paralogs have qualitatively distinct functions. Furthermore, these observations implicate both DCP1a and DCP1b in transcript buffering.