General decapping activators target different subsets of inefficiently translated mRNAs
- University of Massachusetts Medical School, United States
Abstract
The Dcp1-Dcp2 decapping enzyme and the decapping activators Pat1, Dhh1, and Lsm1 regulate mRNA decapping, but their mechanistic integration is unknown. We analyzed the gene expression consequences of deleting PAT1, LSM1, or DHH1, or the DCP2 C-terminal domain, and found that: i) the Dcp2 C-terminal domain is an effector of both negative and positive regulation; ii) rather than being global activators of decapping, Pat1, Lsm1, and Dhh1 directly target specific subsets of yeast mRNAs and loss of the functions of each of these factors has substantial indirect consequences for genome-wide mRNA expression; and iii) transcripts targeted by Pat1, Lsm1, and Dhh1 exhibit only partial overlap, are generally translated inefficiently, and, as expected, are targeted to decapping-dependent decay. Our results define the roles of Pat1, Lsm1, and Dhh1 in decapping of general mRNAs and suggest that these factors may monitor mRNA translation and target unique features of individual mRNAs.
Data availability
The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE107841 at the link https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE107841.
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Genome-wilde identification of decapping substrates in the yeast Saccharomyces cervisiaeNCBI Gene Expression Omnibus, GSE107841.
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Ribosome profiling study of rli1 depeletion strainNCBI Gene Expression Omnibus, GSE69414.
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Widespread Co-translational RNA Decay Reveals Ribosome DynamicsNCBI Gene Expression Omnibus, GSE63120.
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A High Resolution Profile of NMD Substrates in YeastNCBI Gene Expression Omnibus, GSE86428.
Article and author information
Author details
Funding
National Institutes of Health (5R01 GM27757-37)
- Allan Jacobson
National Institutes of Health (1R35GM122468- 01)
- Allan Jacobson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, He et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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General decapping activators target different subsets of inefficiently translated mRNAs
eLife 7:e34409.
https://doi.org/10.7554/eLife.34409
Further reading
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- Chromosomes and Gene Expression
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- Biochemistry and Chemical Biology
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The mRNA 5'-cap structure removal by the decapping enzyme DCP2 is a critical step in gene regulation. While DCP2 is the catalytic subunit in the decapping complex, its activity is strongly enhanced by multiple factors, particularly DCP1, which is the major activator in yeast. However, the precise role of DCP1 in metazoans has yet to be fully elucidated. Moreover, in humans, the specific biological functions of the two DCP1 paralogs, DCP1a and DCP1b, remain largely unknown. To investigate the role of human DCP1, we generated cell lines that were deficient in DCP1a, DCP1b, or both to evaluate the importance of DCP1 in the decapping machinery. Our results highlight the importance of human DCP1 in decapping process and show that the EVH1 domain of DCP1 enhances the mRNA-binding affinity of DCP2. Transcriptome and metabolome analyses outline the distinct functions of DCP1a and DCP1b in human cells, regulating specific endogenous mRNA targets and biological processes. Overall, our findings provide insights into the molecular mechanism of human DCP1 in mRNA decapping and shed light on the distinct functions of its paralogs.
