Gene expression must be stringently regulated to ensure efficient control of cellular processes. A key mechanism of gene expression regulation is the control of mRNA degradation (Chen and Shyu, 2017; Corbett, 2018), mediated by the removal of protective structures from mRNA, which suppresses translation or leads to mRNA degradation. In most eukaryotic cells, mRNA is stabilized through the addition during post-transcriptional modification of an N⁷-methyl guanosine (m⁷G) cap at the 5′ end and a polyA tail at the 3′ end (Furuichi et al., 1977; Garneau et al., 2007). General mRNA decay is typically initiated by deadenylation, which is mediated by the coordinated activity of the CCR4/NOT and PAN2/3 complexes (Chen and Shyu, 2011; Decker and Parker, 1993). Shortening of the polyA tail typically initiates mRNA decay, resulting in exonucleolytic degradation in the 5'–3' or 3'–5' direction, respectively, facilitated by the exonuclease XRN1 or the exosome complex (Chang et al., 2019; Garneau et al., 2007; Lim et al., 2016; Subtelny et al., 2014; Webster et al., 2018; Yi et al., 2018). While the cytoplasmic RNA exosome degrades mRNA in the 3'–5' direction, the primary effect of deadenylation is ‘mRNA decapping’, the removal of the m⁷G cap structure at the 5'-end of the mRNA that otherwise prevents mRNA degradation (Stevens, 1988). This connection between deadenylation and decapping is facilitated by Pat1, which, together with the Lsm1-7 complex, recruits the decapping complex through a combination of disordered and structured domains, promoting distinct steps of mRNA decay (Charenton et al., 2017; Charenton and Graille, 2018; Fourati et al., 2014; Lobel and Gross, 2020; Lobel et al., 2019; Sharif and Conti, 2013; Wu et al., 2014).

The mRNA decapping process is crucial for gene regulation because it leads to the irreversible removal of the mRNA cap structure, inhibiting translation initiation and inducing the XRN1-mediated degradation of mRNA through the 5′–3′ mRNA decay pathway (Hsu and Stevens, 1993; Topisirovic et al., 2011). Decapping does not only lead to the degradation of bulk mRNA molecules; it is also involved in specific mRNA decay pathways, such as AU-rich element-mediated decay, nonsense-mediated decay (NMD), and miRNA-triggered mRNA turnover (Arribas-Layton et al., 2013; Chen and Shyu, 2003; Fenger-Grøn et al., 2005; Jonas and Izaurralde, 2015; Loh et al., 2013). Because of its crucial role in gene regulation, decapping is tightly regulated by the activity of both general and pathway-specific factors through various mechanisms. In the context of NMD for instance, target transcripts can be degraded through endonucleolytic cleavage by SMG6 (Eberle et al., 2009; Huntzinger et al., 2008), or be facilitated by SMG5 in conjunction with the NMD effector SMG7 or the decapping factor PNRC2, leading to enhanced deadenylation and decapping (Cho et al., 2009; Fukuhara et al., 2005; Loh et al., 2013). Understanding the determinants of the preferential associations between certain degradation mechanisms and particular transcripts requires further study (Metze et al., 2013). Overall, the pivotal role of decapping in the intricate network of mRNA decay justifies ongoing research in this field.

In eukaryotes, the removal of the mRNA 5′-m⁷GDP cap structure is catalyzed by the decapping enzyme DCP2, a pyrophosphatase belonging to the Nudix family of proteins. This process results in the generation of 5′ monophosphorylated mRNA, which is subsequently targeted for degradation (Arribas-Layton et al., 2013; Lykke-Andersen, 2002; Steiger et al., 2003; van Dijk et al., 2002; Wang et al., 2002). The central component of the complex, DCP2, has two major domains: the N-terminal regulatory domain (NRD) and the catalytic Nudix domain (She et al., 2006; She et al., 2008). The positively charged patch of the Nudix domain plays a crucial role in RNA binding (Deshmukh et al., 2008; Piccirillo et al., 2003). Meanwhile, the NRD enhances decapping activity by specifically recognizing the m⁷G nucleotide of the mRNA cap structure and interacts with the N-terminal EVH1 domain of the major activator DCP1, further accelerating the decapping process (Chang et al., 2014; Charenton et al., 2016; Dunckley and Parker, 1999; Floor et al., 2010; Mugridge et al., 2016; She et al., 2008; Wang et al., 2002; Wurm et al., 2017). Yeast Dcp2 has an additional unstructured C-terminal extension that contains short helical leucine-rich motifs (HLMs) responsible for protein–protein interactions and elements that inhibit Dcp2 catalytic activity (Charenton et al., 2017; He and Jacobson, 2015). Interestingly, in contrast to yeast, metazoans have the HLM in DCP1, implying a conserved biological function with evolving regulation of mRNA decapping (Fromm et al., 2012).

The interactions between DCP1 and DCP2 proteins and their functions across various species have garnered extensive attention in the study of mRNA degradation mechanisms. While DCP2 is capable of demonstrating catalytic activity on its own (Lykke-Andersen, 2002; van Dijk et al., 2002; Wang et al., 2002), it is important to note that additional cofactors are involved in stimulating DCP2 for complete activation. In yeast, the primary activator of DCP2 is Dcp1, which is essential for decapping activity in vivo (Beelman et al., 1996) and considerably enhances the catalytic activity of Dcp2 in vitro (Deshmukh et al., 2008; Floor et al., 2010; She et al., 2006). Moreover, DCP1 has been shown to interact with other decapping proteins, such as DCP2, to form functional decapping complexes critical for mRNA degradation. Localization and functional analysis of decapping proteins across various species indicate that Dcp1-dependent decapping mechanisms have been conserved throughout evolution and play a significant role in the mRNA decapping machinery (Lall et al., 2005; Sakuno et al., 2004). Furthermore, the importance of DCP1 in plant species underscores the necessity of the decapping complex for proper plant development and highlights its potential homology with yeast and human DCP1 (Xu et al., 2006). These findings suggest that the interaction between DCP1 and DCP2 and their role in mRNA degradation is a conserved key biological process across species.

In addition to Dcp1, proteins such as Edc1-3, Pby1, Lsm1-7, Pat1, and Dhh1 (PNRC1, PNRC2, EDC3, EDC4, Lsm1-7, Lsm14, PatL1, and DDX6 in metazoans) promote decapping by directly or indirectly interacting with Dcp2 (Charenton et al., 2020; Charenton et al., 2017; Charenton and Graille, 2018; Charenton et al., 2016; Cho et al., 2009; Gaviraghi et al., 2018; He and Jacobson, 2023; He et al., 2022; Jonas and Izaurralde, 2013; Ling et al., 2011; Lobel et al., 2019; Mugridge et al., 2018b). These proteins facilitate decapping through the assembly of messenger ribonucleoprotein (RNP) units or the structural rearrangement of DCP2. High levels of these proteins have been detected in large RNP granules, processing bodies (P-bodies), which likely serve as sites for the storage of translationally repressed RNAs and the process of mRNA decay (Eulalio et al., 2007; Jonas and Izaurralde, 2013; Luo et al., 2018).

The interactions between the subunits of the decapping complex are crucial for enhancing its activity and for the targeting of specific mRNAs. Although Dcp1 and Dcp2 have been shown to interact strongly in yeast, direct DCP1-DCP2 interactions are weak in metazoans. Instead, the metazoan-specific protein EDC4, which has binding sites for both DCP1 and DCP2, likely functions as a scaffold that brings these proteins together despite their weak interaction propensity (Chang et al., 2014; Fenger-Grøn et al., 2005). In addition to EDC4, DCP1 acts as a binding platform for other coactivator proteins, such as yeast Edc1 and Edc2 and the human PNRC paralogs, PNRC1 and PNRC2 (Gaviraghi et al., 2018; Jonas and Izaurralde, 2013; Mugridge et al., 2016). In metazoans, the HLM domain of DCP1 interacts with the Lsm domains of proteins such as EDC3 and Lsm14 in a mutually exclusive manner. Moreover, in multicellular eukaryotes, DCP1 features a C-terminal extension that induces DCP1 trimerization, referred to as the trimerization domain (TD). Trimerization is a prerequisite for the incorporation of DCP1 into active decapping complexes and for promoting efficient mRNA decapping in vivo (Fromm et al., 2012; Jonas and Izaurralde, 2013; Tritschler et al., 2007). This competition results in the formation of structurally and functionally distinct assemblies, contributing to target specificity (Vidya and Duchaine, 2022).

Recent structural analyses of the Kluyveromyces lactis Dcp1-Dcp2-Edc3 complex indicate that the Lsm domain of Edc3 binds to an extended helix at the C-terminus of the Dcp2 Nudix domain (Charenton et al., 2016). Furthermore, the activation peptide of Edc1 bridges Dcp1 and Dcp2, as observed in the Edc1-Dcp1-Dcp2 complex in Saccharomyces pombe and Kluyveromyces lactis (Mugridge et al., 2018b; Wurm et al., 2017). These structural insights suggest that Edc1 and Edc3 collaborate through distinct mechanisms, aiding the decapping process (Charenton and Graille, 2018; Charenton et al., 2016; Mugridge et al., 2018a; Mugridge et al., 2018b; Tibble et al., 2021). Specifically, Edc1 stabilizes Dcp2’s catalytically active conformation, while Edc3 extends the RNA binding surface of the Dcp2 Nudix domain (Charenton et al., 2016; Mugridge et al., 2018b). This extended RNA interaction potentially accounts for the transcript-specific nature of Edc3-mediated decapping activation, hinting at distinct coactivators' roles in gene-specific regulation.

While structural studies suggest that interactions with Dcp1 are central to the activation of Dcp2 (Charenton and Graille, 2018; Deshmukh et al., 2008; Mugridge et al., 2018a; Mugridge et al., 2016; She et al., 2008; Valkov et al., 2016), the lack of structural information on the human decapping complex hinders our understanding of the specific role of human DCP1 in decapping. It remains unclear how DCP1 contributes to the conformational changes in the DCP2 catalytic cycle or to mRNA and cap structure recognition. A further complication is the existence of two paralogs of human DCP1, DCP1a, and DCP1b, which have 31% sequence identity over their entire length (Lykke-Andersen, 2002; van Dijk et al., 2002). The functional differences of these paralogs have yet to be determined. Studies of their potentially distinct roles in the decapping complex may provide new insight into the molecular mechanisms of mRNA decapping. The fact that decapping dysfunctions can have detrimental effects on cell growth and have been linked to severe neurological disorders in humans (Ahmed et al., 2015; Ng et al., 2015) highlights the importance of understanding the mechanisms of mRNA decapping regulation and the potential therapeutic implications.

In this study, we investigated the roles of human DCP1 in mRNA decapping by generating HEK-293T cell lines lacking DCP1a, DCP1b, or both. Our findings indicate that human DCP1 promotes decapping in vivo and that DCP1a and DCP1b play redundant roles in the general 5′–3′ mRNA decay pathway. We found that EVH1 domain may be crucial for enhancing DCP2’s recruitment to target mRNA in cells. Multiomics analyses revealed distinct expressional and metabolomic profiles for the knockout cell lines. These results indicate that the DCP1 paralogs have distinct roles in the regulation of various biological processes. Overall, our findings offer valuable insights into the mechanisms underlying human DCP1-mediated mRNA decapping and the specific mRNA targets and biological processes regulated by DCP1a and DCP1b in humans.

DCP1 is a key component in the mRNA decay pathway, crucial for the regulation of gene expression. Research across various species, from yeast to humans, has provided insights into the conservation and evolution of mRNA decapping mechanisms. Notably, DCP1 interacts with other decapping proteins such as DCP2, forming a decapping complex for mRNA degradation. Additionally, the localization and functional analysis of DCP1 in different model organisms, as well as its importance in plant species, highlight its role in post-transcriptional gene expression regulation across species (Lall et al., 2005; Sakuno et al., 2004; Xu et al., 2006). However, in human cells, the specific biological functions of DCP1, especially the distinctions between its two paralogs, DCP1a and DCP1b, have not been fully elucidated. In this study, we found that DCP1 plays a key role in promoting mRNA decapping in human cells. By generating cell lines deficient in DCP1a, DCP1b, or both, our research emphasizes the importance of human DCP1 in the decapping process. We also verified that DCP1 is not only a key platform for assembling various mRNA decapping cofactors, but also established that the EVH1 domain of DCP1 is critical for the mRNA decapping process. Through RNA immunoprecipitation assays, we discovered that the interactions between DCP2 and mRNA heavily rely on the presence of DCP1’s EVH1 domain. These findings imply that DCP1 facilitates the binding of DCP2 to target mRNAs through multiple mechanisms, thereby enhancing the efficiency of mRNA decapping. Finally, our integrated transcriptome and metabolome analyses comparing the specific functions of DCP1a and DCP1b in human cells revealed that they can regulate distinct endogenous mRNA targets and biological processes.

In a prior investigation, we made an intriguing discovery. In human cells, substituting the conserved NR-loop with a flexible GSSG loop in the EVH1 domain of DCP1 had no adverse effect on the interaction between DCP1 and DCP2, nor did it impede their integration into decapping factors. However, this seemingly subtle alteration had a significant consequence – it disrupted the activation of DCP2 (Chang et al., 2014). This points to the pivotal role played by the EVH1 domain of DCP1 in the activation of DCP2, which, in turn, is a critical step in the mRNA decapping process. These findings, combined with our findings in the present study, provide compelling evidence that the DCP1 EVH1 domain is not just a passive component but a crucial player in coordinating interactions and facilitating conformational changes necessary for efficient mRNA decapping. A comprehensive functional characterization of these mechanisms is imperative to fully elucidate the mechanisms underlying DCP1-mediated activation of decapping.

While the protein components of the mRNA decapping machinery have been identified, our current understanding of the distinct roles played by individual decapping factors throughout the process remains limited. Notably, whether the different decapping factors confer target specificity has yet to be clarified. Although previous studies have suggested that DCP1a and DCP1b, the two paralogs of DCP1, play redundant roles in general mRNA decay, this notion is mainly based on reporter assays and single-gene approaches. The specific regulation of endogenous mRNA targets and biological processes by DCP1a and DCP1b is yet to be elucidated.

In this study, we investigated potential functional differences between DCP1a and DCP1b through a combined transcriptome and metabolome analysis. While DCP1a and DCP1b have both been implicated in cancer, our observation of significant alterations in multiple cancer-related pathways in DCP1a-knockout cells suggests that DCP1a might be more prominently associated with cancer development. Furthermore, the downregulation of DCP1a in multiple cancer types further supports the concept that DCP1a is a cancer-associated gene and suggests that its dysregulation may play a contributory role in the onset and progression of diverse cancers. (Ibayashi et al., 2021; Wu et al., 2018; Wu et al., 2021b). Survival analysis has indicated that elevated DCP1a expression in uterine carcinosarcoma carcinoma correlates with improved PFI. Conversely, higher levels of DCP1b expression are associated with both favorable and unfavorable PFIs. Together with the observation of dysregulation of DCP1b in numerous cancers, we speculate that DCP1b is also implicated in cancer pathogenesis, and further studies are required to fully understand the roles of DCP1a and DCP1b in cancer pathogenesis.

With the transcriptome profiles of DCP1a and DCP1b knockout cells, we anticipate significant upregulation among potential targets. However, to discern direct targets from genes upregulated due to indirect effects, it is imperative to delve deeper into mRNA decay rates. Various tools and methods, such as time-series RNA-seq (Viegas et al., 2023) or specialized sequencing techniques like Precision Run-On sequencing (PRO-seq) (Blumberg et al., 2021) or RNA Approach to Equilibrium Sequencing (RATE-Seq) (Abdul-Rahman and Gresham, 2018), have been proposed to estimate mRNA decay rates. Luo et al. utilized TimeLapse-seq to identify potential targets for DCP2 (Luo et al., 2021; Schofield et al., 2018). Incorporating these approaches could provide a more comprehensive understanding in this context.

Notably, our candidate target genes exhibited minimal overlap with the 91 targets of DCP2 (Luo et al., 2021); only EPPK1 overlapped among potential targets of DCP1b_KO, while TES, PAX6, and C18orf21 were the only overlapping genes in the DCP1a/b double knockout.

Our scrutiny of the transcript profiles and metabolite levels within DCP1a- and DCP1b-knockout cells has unveiled their unique contributions to cellular processes. While DCP1a and DCP1b might exhibit certain common gene targets, the distinct transcriptome profiles suggest their functions are not entirely interchangeable. Pathway analysis indicated that DCP1a and DCP1b may have partially complementary roles in regulating cellular pathways. Additionally, several metabolites showed notable alterations in knockout cells, potentially opening a new avenue for investigating the metabolic consequences of DCP1 knockout. Our findings yield valuable understanding of the distinct functions of DCP1a and DCP1b in human cells and the complex regulatory mechanisms underlying cellular metabolism. The potential targets we identified could be investigated further by quantifying specific transcripts and metabolites, and a larger sample size would facilitate the identification of correlations between differentially expressed genes and differentially abundant metabolites.

Overall, our study provides valuable insights into the molecular mechanisms governing DCP1-mediated decapping in human cells and the coordinated regulation of DCP1a and DCP1b, which has important implications for gene expression and cellular function. Future biochemical characterization of the specific mRNA targets and biological pathways regulated by DCP1a and DCP1b is necessary to fully elucidate their roles. This information may help uncover the precise mechanisms underlying mRNA decapping and gene regulation. Furthermore, studying the dysregulation of DCP1 paralogs, especially in cancer, may reveal potential therapeutic targets and improve treatment strategies.

Sequencing data have been deposited in GEO under accession codes GSE230847.

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Author details

1. Ting-Wen Chen

   1. Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
   2. Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
   3. Center for Intelligent Drug Systems and Smart Bio-devices (IDS2 B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan

   Contribution

   Data curation, Software, Formal analysis, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Hsiao-Wei Liao

   Competing interests

   No competing interests declared

2. Hsiao-Wei Liao

   Department of Pharmacy, National Yang Ming Chiao Tung University, Taipei City, Taiwan

   Contribution

   Resources, Data curation, Software, Formal analysis, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Ting-Wen Chen

   Competing interests

   No competing interests declared

3. Michelle Noble

   Department of Biochemistry, Max Planck Institute for Developmental Biology, Tübingen, Germany

   Contribution

   Resources, Data curation, Formal analysis, Validation, Investigation, Visualization, Writing - review and editing

   Competing interests

   No competing interests declared

4. Jing-Yi Siao

   Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan

   Contribution

   Data curation, Formal analysis, Validation, Visualization, Writing - original draft

   Competing interests

   No competing interests declared

5. Yu-Hsuan Cheng

   Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan

   Contribution

   Formal analysis, Validation, Visualization, Writing - review and editing

   Competing interests

   No competing interests declared

6. Wei-Chung Chiang

   Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan

   Contribution

   Resources, Data curation, Software, Methodology

   Competing interests

   No competing interests declared

7. Yi-Tzu Lo

   Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan

   Contribution

   Formal analysis, Visualization

   Competing interests

   No competing interests declared

8. Chung-Te Chang

   1. Department of Biochemistry, Max Planck Institute for Developmental Biology, Tübingen, Germany
   2. Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   chungte.chang@gmail.com

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4792-1646

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