Non-Redundant Roles for the Human mRNA Decapping Cofactor Paralogs DCP1a and DCP1b
Abstract
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. In mammals, 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 they 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 protein degradation and translational machinery. Our data show that the decapping complex exists in at least two configurations. Furthermore, DCP1b protein levels appear distinct in the two configurations of the decapping complex. Both DCP1a and DCP1b impact the turnover of specific groups of mRNAs. Loss of DCP1a or DCP1b, in general, prolongs the half-life of the examined mRNAs. Surprisingly, DCP1a or DCP1b loss increases the synthesis rates of those distinct groups of mRNAs. The data suggest that the decapping complex, specifically DCP1a and DCP1b, are involved in transcript buffering phenomena where steady-state levels of mRNAs are kept stable through reciprocal changes in mRNA turnover and synthesis. 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 paralogs have qualitatively distinct functions.
Subject Area
Biochemistry|Molecular biology|Genetics
Recommended Citation
Vukovic, Ivana, "Non-Redundant Roles for the Human mRNA Decapping Cofactor Paralogs DCP1a and DCP1b" (2024). ProQuest ETD Collection - Thomas Jefferson University. AAI31242732.
https://jdc.jefferson.edu/dissertations/AAI31242732
