The ROQ domain of Roquin recognizes mRNA constitutive-decay element and double-stranded RNA

Tan, Dazhi; Zhou, Mi; Kiledjian, Megerditch; Tong, Liang

doi:10.1038/nsmb.2857

Cited by 80 publications

(111 citation statements)

References 33 publications

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“…The findings of these authors are in general agreement with the data presented here, particularly with regard to the involvement of the wHTH motif in CDE-containing stemloop RNA binding 18,20 , the ability of the ROQ domain to bind also RNA duplexes 18 and to dimerize, either concentrationdependent 20 or induced by duplex RNA binding 18 . The dimeric arrangement seen in the crystal structure of the ROQ domain bound to duplex RNA 18 differs from our proposed dimer model.…”

Section: Discussionsupporting

confidence: 81%

“…3d). However, we realized that the concentrations applied during this ITC experiment involved RNA annealing at a rather high concentration yielding bulged duplex RNA instead of the stem-loop form ( Supplementary Figs 5c and 6), a phenomenon that has also been described by Tan et al 18 Interestingly, we determined a K d value of 68.9 ± 8.6 nM for the binding of RC3H1 to ICOS duplex RNA (Fig. 3d), which is in the same range as observed for stem-loop RNA.…”

Section: Resultsmentioning

confidence: 96%

“…During revision of this manuscript, two independent publications appeared describing structural aspects of roquin-RNA interactions 18,20 . The findings of these authors are in general agreement with the data presented here, particularly with regard to the involvement of the wHTH motif in CDE-containing stemloop RNA binding 18,20 , the ability of the ROQ domain to bind also RNA duplexes 18 and to dimerize, either concentrationdependent 20 or induced by duplex RNA binding 18 .…”

Section: Discussionmentioning

confidence: 99%

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Roquin binding to target mRNAs involves a winged helix-turn-helix motif

et al. 2014

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Roquin proteins mediate mRNA deadenylation by recognizing a conserved class of stem-loop RNA degradation motifs via their Roquin domain. Here we present the crystal structure of a Roquin domain, revealing a mostly helical protein fold bearing a winged helix-turn-helix motif. By combining structural, biochemical and mutation analyses, we gain insight into the mode of RNA binding. We show that the winged helix-turn-helix motif is involved in the binding of constitutive decay elements-containing stem-loop mRNAs. Moreover, we provide biochemical evidence that Roquin proteins are additionally able to bind to duplex RNA and have the potential to be functional in different oligomeric states.

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Section: Discussionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Roquin binding to target mRNAs involves a winged helix-turn-helix motif

et al. 2014

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“…PCR primers used are listed in Supplemental Table S2. mRNA half-lives were calculated as in Tan et al (2014).…”

Section: Plasmid Constructsmentioning

confidence: 99%

DcpS is a transcript-specific modulator of RNA in mammalian cells

Zhou

Bail

Plasterer

et al. 2015

RNA

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The scavenger decapping enzyme DcpS is a multifunctional protein initially identified by its property to hydrolyze the resulting cap structure following 3 ′ end mRNA decay. In Saccharomyces cerevisiae, the DcpS homolog Dcs1 is an obligate cofactor for the 5 ′ -3 ′ exoribonuclease Xrn1 while the Caenorhabditis elegans homolog Dcs-1, facilitates Xrn1 mediated microRNA turnover. In both cases, this function is independent of the decapping activity. Whether DcpS and its decapping activity can affect mRNA steady state or stability in mammalian cells remains unknown. We sought to determine DcpS target genes in mammalian cells using a cell-permeable DcpS inhibitor compound, RG3039 initially developed for therapeutic treatment of spinal muscular atrophy. Global mRNA levels were examined following DcpS decapping inhibition with RG3039. The steady-state levels of 222 RNAs were altered upon RG3039 treatment. Of a subset selected for validation, two transcripts that appear to be long noncoding RNAs HS370762 and BC011766, were dependent on DcpS and its scavenger decapping catalytic activity and referred to as DcpS-responsive noncoding transcripts (DRNT) 1 and 2, respectively. Interestingly, only the increase in DRNT1 transcript was accompanied with an increase of its RNA stability and this increase was dependent on both DcpS and Xrn1. Importantly, unlike in yeast where the DcpS homolog is an obligate cofactor for Xrn1, stability of additional Xrn1 dependent RNAs were not altered by a reduction in DcpS levels. Collectively, our data demonstrate that DcpS in conjunction with Xrn1 has the potential to regulate RNA stability in a transcript-selective manner in mammalian cells.

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“…181 . Roquin-2 has two binding sites for RNA -one that recognizes stem-loop motifs, and another that recognizes double-stranded RNA -and both are required for promoting RNA decay 190 . We could not identify the conserved CDE stemloop motif in the opossum 3' UTR of Npt2a, but we did find a CDE motif in the mouse 3'UTR.…”

Section: Discussionmentioning

confidence: 99%

Post-transcriptional regulation of the Type IIA sodium-phosphate cotransporter by parathyroid hormone.

Murray¹

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PTH is a critical regulator of serum phosphorus. We have previously shown that PTH decreases proximal tubule NpT2a mRNA expression through post‐transcriptional mechanisms, and that this effect can be reproduced by treatment with 8‐bromo‐cAMP, a PKA activator, but not phorbol myristate acetate, a PKC activator. We hypothesize that PKA is the primary mediator of NpT2a mRNA destabilization by PTH. To determine the contribution of each pathway to the PTH response, opossum kidney (OK) cells were treated with selective protein kinase inhibitors in the presence of PTH, and NpT2a mRNA expression was measured by qRT‐PCR. Pretreatment with 10µM PKC inhibitor peptide (PKCi) followed by 100nM PTH for 6h produced a 43.9% decrease in NpT2a mRNA versus PKCi alone. Pretreatment with 10µM H‐89, a PKA inhibitor, prevented the initial decrease in NpT2a mRNA by PTH but did not prevent the ultimate reduction. 8CPT‐2Me‐cAMP, a selective activator of Epac, failed to produce a decrease in NpT2a mRNA after 6h. We conclude that the initial effect of PTH on NpT2a mRNA is PKA‐dependent, whereas chronic regulation involves both the PKA and PKC pathways. Grant Funding Source: Support for this project is provided by VA to EDL.

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The ROQ domain of Roquin recognizes mRNA constitutive-decay element and double-stranded RNA

Cited by 80 publications

References 33 publications

Roquin binding to target mRNAs involves a winged helix-turn-helix motif

Roquin binding to target mRNAs involves a winged helix-turn-helix motif

DcpS is a transcript-specific modulator of RNA in mammalian cells

Post-transcriptional regulation of the Type IIA sodium-phosphate cotransporter by parathyroid hormone.

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