The DDX5/Dbp2 subfamily of DEAD‐box RNA helicases

Zheng, Xing; Kit, Wai; Tran, Elizabeth

doi:10.1002/wrna.1519

Cited by 77 publications

(67 citation statements)

References 159 publications

(364 reference statements)

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“…Previous results from our laboratory showed that the ortholog of DDX5 in S. cerevisiae, Dbp2 (Xing et al 2019), is required for efficient termination of RNAPII transcription, as loss of DBP2 results in accumulation of a 39 extended GAL10 mRNA and GAL10s long, noncoding RNA (Cloutier et al 2012). Both Dbp2 and DDX5 exhibit highly efficient RNA duplex unwinding in vitro, consistent with a role in altering secondary structure Xing et al 2017).…”

supporting

confidence: 55%

Genome-Wide Discovery of DEAD-Box RNA Helicase Targets Reveals RNA Structural Remodeling in Transcription Termination

et al. 2019

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RNA helicases are a class of enzymes that unwind RNA duplexes in vitro but whose cellular functions are largely enigmatic. Here, we provide evidence that the DEAD-box protein Dbp2 remodels RNA-protein complex (RNP) structure to facilitate efficient termination of transcription in Saccharomyces cerevisiae via the Nrd1-Nab3-Sen1 (NNS) complex. First, we find that loss of DBP2 results in RNA polymerase II accumulation at the 39 ends of small nucleolar RNAs and a subset of mRNAs. In addition, Dbp2 associates with RNA sequence motifs and regions bound by Nrd1 and can promote its recruitment to NNS-targeted regions. Using Structure-seq, we find altered RNA/RNP structures in dbp2D cells that correlate with inefficient termination. We also show a positive correlation between the stability of structures in the 39 ends and a requirement for Dbp2 in termination. Taken together, these studies provide a role for RNA remodeling by Dbp2 and further suggests a mechanism whereby RNA structure is exploited for gene regulation.

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confidence: 55%

Genome-Wide Discovery of DEAD-Box RNA Helicase Targets Reveals RNA Structural Remodeling in Transcription Termination

et al. 2019

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“…DDX17 is a member of the large family of DEAD-box RNA helicases found within the superfamily 2 ATPases Linder and Jankowsky, 2011;Xing et al, 2019). DEADbox proteins are necessary for proper function of RNA in many cellular processes (Cordin et al, 2006;Fuller-Pace, 2013b;Gustafson and Wessel, 2010;Janknecht, 2010;Jarmoskaite and Russell, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Similar to other DEAD-box proteins, DDX17 is an RNA-dependent ATPase. For its helicase function, DDX17 is thought to remodel RNA in a non-processive manner (Huang and Liu, 2002;Pyle, 2008;Rö ssler et al, 2001;Xing et al, 2017Xing et al, , 2019. DDX17 has been reported to bind various RNA sequences and structures, including stem-loop structures (Mori et al, 2014;Moy et al, 2014;Remenyi et al, 2016), G-quadruplexes (Herdy et al, 2018), and R-loops (Wang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

RNA Specificity and Autoregulation of DDX17, a Modulator of MicroRNA Biogenesis

2019

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Graphical Abstract Highlights d Crystal structures of human DDX17 core domains in multiple states are determined d DDX17 core domains exhibit RNA sequence preference via the RMFQ motif d DDX17 can enhance processing of pri-miRs by remodeling the 3 0 flanking region d N-terminal tail of DDX17 can regulate the ATPase activity In Brief Ngo et al. reveal crystal structures of DEAD-box 17 (DDX17) and show that the core catalytic domains recognize RNA sequence motifs in primary transcripts of microRNAs, to regulate processing by Drosha. DDX17 also has a unique N-terminal tail that can attenuate the ATPase activity. SUMMARY DDX17, a DEAD-box ATPase, is a multifunctional helicase important for various RNA functions, including microRNA maturation. Key questions for DDX17 include how it recognizes target RNAs and influences their structures, as well as how its ATPase activity may be regulated. Through crystal structures and biochemical assays, we show the ability of the core catalytic domains of DDX17 to recognize specific sequences in target RNAs. The RNA sequence preference of the catalytic core is critical for DDX17 to directly bind and remodel a specific region of primary microRNAs 3 0 to the mature sequence, and consequently enhance processing by Drosha. Furthermore, we identify an intramolecular interaction between the N-terminal tail and the DEAD domain of DDX17 to have an autoregulatory role in controlling the ATPase activity. Thus, we provide the molecular basis for how cognate RNA recognition and functional outcomes are linked for DDX17. À . We identify several mutations of DDX17 that affect ATP 4024 Cell Reports 29, 4024-4035, December 17, 2019 ª 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). domains. STAR+METHODSDetailed methods are provided in the online version of this paper and include the following:TABLE d LEAD CONTACT AND MATERIALS AVAILABILITY d EXPERIMENTAL MODEL AND SUBJECT DETAILS d METHOD DETAILS B Materials B in vitro RNA transcription and purification B Protein purification B RNA Unwinding Assay B Size-exclusion chromatography-Multiangle light scattering B Electrophoretic Mobility Shift Assay B in vitro ATP hydrolysis Assay B Differential Scanning Fluorimetry B Crystallization and Data Collection B Structure determination and refinement B in vitro pri-miR processing assays B Hydroxyl radical footprinting B Selective hydroxyl acylation followed by primer extension (SHAPE) B Cell Culture and quantitative real-time PCR (qPCR)

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“…The p68 RNA helicase (also called DEAD-box protein 5; DDX5) is a prototypic member of the DEAD box family of RNA helicases that exhibits ATPase and RNA unwinding activities 5 . The DEAD box family is named after the amino acid sequence of its conserved Motif II (also known as the Walker B motif) containing the amino acids asp-glu-ala-asp (D-E-A-D).…”

Section: Introductionmentioning

confidence: 99%

RNA helicase p68 inhibits the transcription and post-transcription of Pkd1 in ADPKD

Zhang¹,

Li²,

Zhou³

et al. 2020

Theranostics

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Background: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations of the PKD1 and PKD2 genes. Dysregulation of the expression of PKD genes, the abnormal activation of PKD associated signaling pathways, and the expression and maturation of miRNAs regulates cyst progression. However, the upstream factors regulating these abnormal processes in ADPKD remain elusive. Methods: To investigate the roles of an RNA helicase, p68, in ADPKD, we performed Western blot and qRT-PCR analysis, immunostaining and ChIP assay in cystic renal epithelium cells and tissues. Results: We found that p68 was upregulated in cystic renal epithelial cells and tissues. p68 represses Pkd1 gene expression via transcriptional and posttranscriptional mechanisms in renal epithelial cells, in that 1) p68 binds to the promoter of the Pkd1 gene together with p53 to repress transcription; and 2) p68 promotes the expression and maturation of miR-17, miR-200c and miR-182 and via these miRNAs, post-transcriptionally regulates the expression of Pkd1 mRNA. Drosha is involved in this process by forming a complex with p68. p68 also regulates the phosphorylation and activation of PKD proliferation associated signaling and the expression of fibrotic markers in Pkd1 mutant renal epithelial cells. Silence of p68 delays cyst formation in collecting duct cell mediated 3D cultures. In addition, the expression of p68 is induced by H 2 O 2 -dependent oxidative stress and DNA damage which causes downregulation of Pkd1 transcription in cystic renal epithelial cells and tissues. Conclusions: p68 plays a critical role in negatively regulating the expression of the PKD1 gene along with positively regulating the expression and maturation of miRNAs and activation of PKD associated signaling pathways to cause renal cyst progression and fibrosis in ADPKD.

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The DDX5/Dbp2 subfamily of DEAD‐box RNA helicases

Cited by 77 publications

References 159 publications

Genome-Wide Discovery of DEAD-Box RNA Helicase Targets Reveals RNA Structural Remodeling in Transcription Termination

Genome-Wide Discovery of DEAD-Box RNA Helicase Targets Reveals RNA Structural Remodeling in Transcription Termination

RNA Specificity and Autoregulation of DDX17, a Modulator of MicroRNA Biogenesis

RNA helicase p68 inhibits the transcription and post-transcription of Pkd1 in ADPKD

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