The human decapping scavenger enzyme DcpS modulates microRNA turnover

Méziane, Oussama; Piquet, Sandra; Bossé, Gabriel D.; Gagné, Dominic; Paquet, Éric R.; Robert, Claude; Tones, Michael A.; Simard, Martin J.

doi:10.1038/srep16688

Cited by 21 publications

(23 citation statements)

References 23 publications

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“…These data suggest either that DAQ-DcpSi do not regulate miRNA levels, or that any changes are too subtle to be detected using RNA-Seq methodology. The latter interpretation appears most likely based on a demonstrable effect of DAQ-DcpSi reported recently [ 24 ].…”

Section: Resultsmentioning

confidence: 71%

“…Some catalytically-inactive DcpS mutants can also promote Xrn1 activity, indicating that this effect is independent of enzyme activity of DcpS [ 31 ]. These observations have now been extended to human cells showing that DcpS regulates miRNA stability and that although this is a non-catalytic activity function of DcpS it is inhibited by DAQ-DcpSi, possibly due to allosteric modulation of the interaction with XRN2 [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

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In vitro and in vivo effects of 2,4 diaminoquinazoline inhibitors of the decapping scavenger enzyme DcpS: Context-specific modulation of SMN transcript levels

et al. 2017

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C5-substituted 2,4-diaminoquinazoline inhibitors of the decapping scavenger enzyme DcpS (DAQ-DcpSi) have been developed for the treatment of spinal muscular atrophy (SMA), which is caused by genetic deficiency in the Survival Motor Neuron (SMN) protein. These compounds are claimed to act as SMN2 transcriptional activators but data underlying that claim are equivocal. In addition it is unclear whether the claimed effects on SMN2 are a direct consequence of DcpS inhibitor or might be a consequence of lysosomotropism, which is known to be neuroprotective. DAQ-DcpSi effects were characterized in cells in vitro utilizing DcpS knockdown and 7-methyl analogues as probes for DcpS vs non-DcpS-mediated effects. We also performed analysis of Smn transcript levels, RNA-Seq analysis of the transcriptome and SMN protein in order to identify affected pathways underlying the therapeutic effect, and studied lysosomotropic and non-lysosomotropic DAQ-DCpSi effects in 2B/- SMA mice. Treatment of cells caused modest and transient SMN2 mRNA increases with either no change or a decrease in SMNΔ7 and no change in SMN1 transcripts or SMN protein. RNA-Seq analysis of DAQ-DcpSi-treated N2a cells revealed significant changes in expression (both up and down) of approximately 2,000 genes across a broad range of pathways. Treatment of 2B/- SMA mice with both lysomotropic and non-lysosomotropic DAQ-DcpSi compounds had similar effects on disease phenotype indicating that the therapeutic mechanism of action is not a consequence of lysosomotropism. In striking contrast to the findings in vitro, Smn transcripts were robustly changed in tissues but there was no increase in SMN protein levels in spinal cord. We conclude that DAQ-DcpSi have reproducible benefit in SMA mice and a broad spectrum of biological effects in vitro and in vivo, but these are complex, context specific, and not the result of simple SMN2 transcriptional activation.

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Section: Resultsmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo effects of 2,4 diaminoquinazoline inhibitors of the decapping scavenger enzyme DcpS: Context-specific modulation of SMN transcript levels

et al. 2017

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“…DCS-1, a decapping scavenger enzyme, interacts with CeXRN1 and promotes the degradation of miRNAs in C. elegans [48]. The human orthologue of DCS-1 is also required for the 5'-3' exoribonuclease function of XRN2 and plays key roles in miRNA degradation [49]. As a marker protein for the 5 -3 mRNA degradation pathway, AtXRN4 has been reported to co-localize with DCP1 in P-bodies [37].…”

Section: Discussionmentioning

confidence: 99%

AtXRN4 Affects the Turnover of Chosen miRNA*s in Arabidopsis

Liu

Gao

et al. 2020

Plants

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Small RNA (sRNA) turnover is a key but poorly understood mechanism that determines the homeostasis of sRNAs. Animal XRN genes contribute the degradation of sRNAs, AtXRN2 and AtXRN3 also contribute the pri-miRNA processing and miRNA loop degradation in plants. However, the possible functions of the plant XRN genes in sRNA degradation are far from known. Here, we find that AtXRN4 contributes the turnover of plant sRNAs in Arabidopsis thaliana mainly by sRNA-seq, qRT-PCR and Northern blot. The mutation of AtXRN4 alters the sRNA profile and the accumulation of 21 nt sRNAs was increased. Some miRNA*s levels are significantly increased in xrn4 mutant plants. However, the accumulation of the primary miRNAs (pri-miRNAs) and miRNA precursors (pre-miRNAs) were generally unchanged in xrn4 mutant plants which indicates that AtXRN4 contributes the degradation of some miRNA*s. Moreover, AtXRN4 interacts with Arabidopsis Argonaute 2 (AtAGO2). This interaction takes place in Processing bodies (P-bodies). Taken together, our observations identified the interaction between XRN4 with AtAGO2 and suggested that plant XRN4 also contributes the turnover of sRNAs.

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“…In yeast this is mainly, but probably not exclusively, carried out by a nucleoside diphosphate kinase; in other organisms the enzymes still need to be identified (Taverniti & Séraphin, ). Several other functions of DcpS have been reported: (a) yeast Dcs1 is an obligate cofactor of the 5′→3′ exoribonuclease Xrn1 and facilitates 5′→3′ decay by an unknown mechanism independently of its decapping activity (H. Liu & Kiledjian, ; Sinturel, Bréchemier‐Baey, Kiledjian, Condon, & Bénard, ); (b) the Caenorhabditis elegans DcpS homologue, Dcs‐1 also interacts with Xrn‐1 independently of decapping and degrades specific miRNAs (Bossé et al, ); similar observations were made for human DcpS, which requires Xrn2, the human orthologue of yeast Rat1 (Meziane et al, ); (c) DcpS was also suggested to regulate general mRNA metabolism as its activity influences the amount of cap degradation intermediates, which in turn bind to and recruit cap‐binding proteins (Bail & Kiledjian, ). DcpS may therefore impact upon all cellular events that depend on cap‐binding proteins, including nuclear mRNA processing, nuclear export and translation (Bail & Kiledjian, ; S.‐W.…”

Section: Histidine Triad Proteinsmentioning

confidence: 99%

The complex enzymology of mRNA decapping: Enzymes of four classes cleave pyrophosphate bonds

Krämer

McLennan

2018

WIREs RNA

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The 5 0 ends of most RNAs are chemically modified to enable protection from nucleases. In bacteria, this is often achieved by keeping the triphosphate terminus originating from transcriptional initiation, while most eukaryotic mRNAs and small nuclear RNAs have a 5 0 !5 0 linked N 7 -methyl guanosine (m 7 G) cap added. Several other chemical modifications have been described at RNA 5 0 ends. Common to all modifications is the presence of at least one pyrophosphate bond. To enable RNA turnover, these chemical modifications at the RNA 5 0 end need to be reversible. Dependent on the direction of the RNA decay pathway (5 0 !3 0 or 3 0 !5 0 ), some enzymes cleave the 5 0 !5 0 cap linkage of intact RNAs to initiate decay, while others act as scavengers and hydrolyse the cap element of the remnants of the 3 0 !5 0 decay pathway. In eukaryotes, there is also a cap quality control pathway. Most enzymes involved in the cleavage of the RNA 5 0 ends are pyrophosphohydrolases, with only a few having (additional) 5 0 triphosphonucleotide hydrolase activities. Despite the identity of their enzyme activities, the enzymes belong to four different enzyme classes. Nudix hydrolases decap intact RNAs as part of the 5 0 !3 0 decay pathway, DXO family members mainly degrade faulty RNAs, members of the histidine triad (HIT) family are scavenger proteins, while an ApaH-like phosphatase is the major mRNA decay enzyme of trypanosomes, whose RNAs have a unique cap structure. Many novel cap structures and decapping enzymes have only recently been discovered, indicating that we are only beginning to understand the mechanisms of RNA decapping. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability RNA Processing > Capping and 5 0 End Modifications K E Y W O R D S ApaH, decapping, HIT proteins, nudix, trypanosomes 1 | INTRODUCTIONSingle stranded RNAs with a free 5 0 monophosphate end are susceptible to rapid degradation. Transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs) are stabilized by hairpin structures and by "hiding" their 5 0 ends within complex protein structures. All other RNA species avoid monophosphates at their 5 0 ends and instead carry chemical modifications arising either from the nucleotide initiating transcription or from further 5 0 end processing. These 5 0 end modifications can be as simple as a di-or triphosphate-often found in bacterial RNAs-or more complex like the 5 0 -5 0 linked N 7 -methyl guanosine (m 7 G) cap of eukaryotes or the NAD + cap found in both eukaryotes and bacteria. Despite the apparent differences, all chemical

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The human decapping scavenger enzyme DcpS modulates microRNA turnover

Cited by 21 publications

References 23 publications

In vitro and in vivo effects of 2,4 diaminoquinazoline inhibitors of the decapping scavenger enzyme DcpS: Context-specific modulation of SMN transcript levels

In vitro and in vivo effects of 2,4 diaminoquinazoline inhibitors of the decapping scavenger enzyme DcpS: Context-specific modulation of SMN transcript levels

AtXRN4 Affects the Turnover of Chosen miRNA*s in Arabidopsis

The complex enzymology of mRNA decapping: Enzymes of four classes cleave pyrophosphate bonds

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