Microprocessor depends on hemin to recognize the apical loop of primary microRNA

Nguyen, Tuan Anh; Park, Joha; Dang, Thi Lieu; Choi, Yeon-Gil; Kim, V. Narry

doi:10.1093/nar/gky248

Cited by 65 publications

(76 citation statements)

References 43 publications

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“…In cells overexpressing P351A, miRNAs have increased, largely unchanged, or decreased expression as compared to the KO (Fig. 6C) (Nguyen et al 2018). Increasing DGCR8 heme occupancy by either treating the P351A-expressing cells with a heme biosynthesis precursor 5-aminolevulinic acid (ALA) or overexpressing WT DGCR8 causes differential upregulation of most miRNAs (Fig.…”

Section: Heme Modulates the Hierarchy And Specificity For Processing mentioning

confidence: 94%

“…We are interested in understanding how DGCR8 heme-binding-deficient mutations and cellular heme conditions affect miRNA maturation at the genomic scale. Recently, Kim and colleagues reported such experiments (Nguyen et al 2018). They first knocked out DGCR8 in HCT116, a human colon cancer cell line, by deleting segments of CTT.…”

Section: Genomic Evidence Supports the Requirement Of Heme For Mirna mentioning

confidence: 99%

“…Kim and colleagues rightfully concluded that heme differentiates miRNA maturation and their study focused on how heme induces the processing of pri-miRNAs containing a UGU motif at their apical junctions (Nguyen et al 2018). With new understanding of the mutational effects on DGCR8 activity, we have uncovered previously unknown principles governing how heme affects miRNA maturation.…”

Section: Heme Modulates the Hierarchy And Specificity For Processing mentioning

confidence: 99%

“…The previous reported data were obtained from the Gene Expression Omnibus (GEO: http://www.ncbi.nlm.nih.gov/geo) under the accession number GSE111431 (Nguyen et al 2018). In the downloaded data, the miRNA reads have already been normalized.…”

Section: Analysis Of Small Rna Sequencing Data Of Dgcr8 Ko and Rescuementioning

confidence: 99%

“…1A) (Quick-Cleveland et al 2014;Nguyen et al 2015). In the absence of heme, Rhed can still bind RNA (Quick-Cleveland et al 2014) but Microprocessor displays reduced pri-miRNA cleavage activity biochemically and increased cleavage of pri-miRNAs in the non-productive orientation (Partin et al 2017;Nguyen et al 2018).…”

Section: Introductionmentioning

confidence: 99%

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Fe(III) heme sets an activation threshold for processing distinct groups of pri-miRNAs in mammalian cells

Weitz¹,

Quick-Cleveland

Jacob

et al. 2020

Preprint

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The essential biological cofactor heme is synthesized in cells in the Fe(II) form. Oxidized Fe(III) heme is specifically required for processing primary transcripts of microRNAs (pri-miRNAs) by the RNA-binding protein DGCR8, a core component of the Microprocessor complex. It is unknown how readily available Fe(III) heme is in the largely reducing environment in human cells and how changes in cellular Fe(III) heme availability alter microRNA (miRNA) expression. Here we address the first question by characterizing DGCR8 mutants with various degrees of deficiency in heme-binding. We observed a strikingly simple correlation between Fe(III) heme affinity in vitro and the Microprocessor activity in HeLa cells, with the heme affinity threshold for activation estimated to be between 0.6-5 pM under typical cell culture conditions. The threshold is strongly influenced by cellular heme synthesis and uptake. We suggest that the threshold reflects a labile Fe(III) heme pool in cells. Based on our understanding of DGCR8 mutants, we reanalyzed recently reported miRNA sequencing data and conclude that heme is generally required for processing canonical pri-miRNAs, that heme modulates the specificity of Microprocessor, and that cellular heme level and differential DGCR8 heme occupancy alter the expression of distinct groups of miRNAs in a hierarchical fashion. Overall, our study provides the first glimpse of a labile Fe(III) heme pool important for a fundamental physiological function and reveal principles governing how Fe(III) heme modulates miRNA maturation at a genomic scale. We also discuss potential states and biological significance of the labile Fe(III) heme pool.

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Section: Heme Modulates the Hierarchy And Specificity For Processing mentioning

confidence: 94%

Section: Genomic Evidence Supports the Requirement Of Heme For Mirna mentioning

confidence: 99%

Section: Heme Modulates the Hierarchy And Specificity For Processing mentioning

confidence: 99%

Section: Analysis Of Small Rna Sequencing Data Of Dgcr8 Ko and Rescuementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Fe(III) heme sets an activation threshold for processing distinct groups of pri-miRNAs in mammalian cells

Weitz¹,

Quick-Cleveland

Jacob

et al. 2020

Preprint

View full text Add to dashboard Cite

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The orf virus (ORFV) protein OV20.0 interacts with the microprocessor complex subunit DGCR8 to regulate miRNA biogenesis and ORFV infection

Liao

Tseng

et al. 2021

FEBS Letters

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Cellular double-stranded RNA-binding proteins (DRBPs) play important roles in the regulation of innate immune responses and microRNA (miRNA) biogenesis. The current study aimed to understand whether OV20.0, a DRBP of orf virus (ORFV), is involved in cellular RNA biogenesis via association with host DRBPs. We found that OV20.0 interacts with DiGeorge syndrome critical region 8 (DGCR8), a subunit of the miRNA processor complex, and binds to primary-and precursor-miRNA. Additionally, OV20.0 regulates DGCR8 expression in multiple ways, including through interaction with the DGCR8 protein and binding to DGCR8 mRNA. Lastly, our data show that DGCR8 plays an antiviral role against ORFV infection, whereas it is beneficial for influenza virus propagation, indicating that the underlying mechanisms could be diverse among different viruses.

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An overview of microRNAs: Biology, functions, therapeutics, and analysis methods

Saliminejad

Khorshid

Fard

et al. 2018

Journal Cellular Physiology

1,431

830

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MicroRNAs (miRNAs) are a class of small noncoding RNAs, which function in posttranscriptional regulation of gene expression. They are powerful regulators of various cellular activities including cell growth, differentiation, development, and apoptosis. They have been linked to many diseases, and currently miRNA-mediated clinical trial has shown promising results for treatment of cancer and viral infection. This review provides an overview and update on miRNAs biogenesis, regulation of miRNAs expression, their biological functions, and role of miRNAs in epigenetics and cell-cell communication. In addition, alteration of miRNAs following exercise, their associationwith diseases, and therapeutic potential will be explained. Finally, miRNA bioinformatics tools and conventional methods for miRNA detection and quantification will be discussed.

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Microprocessor depends on hemin to recognize the apical loop of primary microRNA

Cited by 65 publications

References 43 publications

Fe(III) heme sets an activation threshold for processing distinct groups of pri-miRNAs in mammalian cells

Fe(III) heme sets an activation threshold for processing distinct groups of pri-miRNAs in mammalian cells

The orf virus (ORFV) protein OV20.0 interacts with the microprocessor complex subunit DGCR8 to regulate miRNA biogenesis and ORFV infection

An overview of microRNAs: Biology, functions, therapeutics, and analysis methods

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