Cryo-EM Structure of Human Dicer and Its Complexes with a Pre-miRNA Substrate

Liu, Zhongmin; Wang, Jia; Huang, Cheng; Xin, Ke Gui; Sun, Lei; Zhang, Qiangfeng Cliff; Wang, Hongwei

doi:10.1016/j.cell.2018.05.031

Cited by 65 publications

(82 citation statements)

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“…Although recent cryo-EM structures of dmDcr-2 and hsDcr represent a significant advance in resolution (Liu et al 2018;Sinha et al 2018), neither structure shows dsRNA engaged at the RNase III active sites and, thus, does not offer insight into the cleavage-competent state. In fact, in the cryo-EM structure of the hsDcr•TRBP•pre-miRNA complex (Fig.…”

Section: Mechanistic Insights From Rnase III Enzymesmentioning

confidence: 99%

“…2C), Dicer's dsRBM occupies the catalytic valley where the dsRNA substrate would be predicted to bind for cleavage, and instead, the pre-let-7 substrate interacts with the opposite face of hDcr's carboxy-terminal dsRBM (Fig. 3D, hsDcr; Liu et al 2018). The absence of dsRNA in the catalytic valley of hsDcr is not surprising as the complex was intentionally reconstituted in the absence of Mg 2+ , and based on studies of aaRNase III, magnesium is necessary for a catalytically competent state (Blaszczyk et al 2001).…”

Section: Mechanistic Insights From Rnase III Enzymesmentioning

confidence: 99%

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Dicer's Helicase Domain: A Meeting Place for Regulatory Proteins

Hansen

Aderounmu

Donelick

et al. 2019

Cold Spring Harb Symp Quant Biol

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The function of Dicer's helicase domain has been enigmatic since its discovery. Why do only some Dicers require ATP, despite a high degree of sequence conservation in their helicase domains? We discuss evolutionary considerations based on differences between vertebrate and invertebrate antiviral defense, and how the helicase domain has been co-opted in extant organisms as the binding site for accessory proteins. Many accessory proteins are double-stranded RNA binding proteins, and we propose models for how they modulate Dicer function and catalysis.

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Section: Mechanistic Insights From Rnase III Enzymesmentioning

confidence: 99%

Section: Mechanistic Insights From Rnase III Enzymesmentioning

confidence: 99%

Dicer's Helicase Domain: A Meeting Place for Regulatory Proteins

Hansen

Aderounmu

Donelick

et al. 2019

Cold Spring Harb Symp Quant Biol

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show abstract

“…The comparison between bacterial RNase III and yeast Rnt1p, both in the form of post‐cleavage complex, reveals that the cleavage site assemblies of the two enzymes are identical except that the eukaryotic protein employs two more catalytic side chains in each of the two cleavage sites and that the dsRBDs are positioned very differently in the two complexes. The conservation of the cleavage site assemblies provides a solid foundation for modeling the catalytic complex of eukaryotic RNase III enzymes including: Kluyveromyces polysporus Dcr1 (Weinberg et al, ), human Drosha (Kwon et al, ), and human Dicer (Liu et al, ), for which the known structures either do not contain RNA ( K. polysporus Dcr1 and human Drosha) or contain RNA but not in a meaningful way for the cleavage of the phosphodiester bond (human Dicer). Hence, the single two‐Mg 2+ ‐ion mechanism of RNase III enzymes can accommodate different substrate specificity in concert with substrate selection.…”

Section: Resultsmentioning

confidence: 99%

“…For human Drosha, RNA is not seen in the structure of either isolated dsRBD (Mueller et al, ) or the Platform‐dsRBD fragment (Kwon et al, ). For human Dicer, RNA is ~40 Å away from the active center (Figure g) and is not in contact with the dsRBD (Liu et al, ).…”

Section: Common and Unique Structural Features Of Rnt1p Substrate Recmentioning

confidence: 99%

“…For human Drosha, a crystal structure has been determined for a truncated fragment without the RS‐rich and P‐rich domains and in the absence of RNA (Figure f; Kwon et al, ). For human Dicer, a cryo‐EM structure has been determined for full‐length protein in complex with the precursor of a miRNA (pre‐miRNA); the structure shows, however, that the RNA is ~40 Å away from the processing center and is not bound by the dsRBD (Figure g; Liu et al, ). Unlike Drosha and Dicer, structures of catalytically meaningful RNA complexes for RNase III and Rnt1p have been determined.…”

Section: Introductionmentioning

confidence: 99%

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Structure and function of Rnt1p: An alternative to RNAi for targeted RNA degradation

Elela

2018

WIREs RNA

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The double-stranded RNA-binding protein (dsRBP) family controls RNA editing, stability, and function in all eukaryotes. The central feature of this family is the recognition of a generic RNA duplex using highly conserved double-stranded RNAbinding domain (dsRBD) that recognizes the characteristic distance between the minor grooves created by the RNA helix. Variations on this theme that confer species and functional specificities have been reported but most dsRBPs retain their capacity to bind generic dsRNA. The ribonuclease III (RNase III) family members fall into four classes, represented by bacterial RNase III, yeast Rnt1p, human Drosha, and human Dicer, respectively. Like all dsRBPs and most members of the RNase III family, Rnt1p has a dsRBD, but unlike most of its kin, it poorly binds to generic RNA helices. Instead, Rnt1p, the only known RNase III expressed in Saccharomyces cerevisiae that lacks the RNAi (RNA interference) machinery, recognizes a specific class of stem-loop structures. To recognize the specific substrates, the dsRBD of Rnt1p is specialized, featuring a αβββααα topology and a sequencespecific RNA-binding motif at the C-terminus. Since the discovery of Rnt1p in 1996, significant progress has been made in studies of its genetics, function, structure, and mechanism of action, explaining the reasons and mechanisms for the increased specificity of this enzyme and its impact on the mechanism of RNA degradation. This article is categorized under:RNA Turnover and Surveillance > Turnover/Surveillance

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DICER1‐associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: Pathology, molecular genetics, and indications for molecular testing

Apellaniz-Ruiz

McCluggage

Foulkes

2020

Genes Chromosomes & Cancer

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Gynecologic sarcomas are uncommon neoplasms, the majority occurring in the uterus. Due to the diverse nature of these, the description of “new” morphological types and the rarity of some of them, pathological diagnosis and treatment is often challenging. Finding genetic alterations specific to, and frequently occurring, in a certain type can aid in the diagnosis. DICER1 is a highly conserved ribonuclease crucial in the biogenesis of microRNAs and mutations in DICER1 (either somatic or germline) have been detected in a wide range of sarcomas including genitourinary embryonal rhabdomyosarcomas (ERMS) and adenosarcomas. Importantly, DICER1‐associated sarcomas share morphological features irrespective of the site of origin such that the pathologist can strongly suspect a DICER1 association. A review of the literature shows that almost all gynecologic ERMS reported (outside of the vagina) harbor DICER1 alterations, while approximately 20% of adenosarcomas also do so. These two tumor types exhibit significant morphological overlap and DICER1 tumor testing may be helpful in distinguishing between them, because a negative result makes ERMS unlikely. Given that germline pathogenic DICER1 variants are frequent in uterine (corpus and cervix) ERMS and pathogenic germline variants in this gene cause a hereditary cancer predisposition syndrome (DICER1 syndrome), patients diagnosed with these neoplasms should be referred to medical genetic services. Cooperation between pathologists and geneticists is crucial and will help in improving the diagnosis and management of these uncommon sarcomas.

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Cryo-EM Structure of Human Dicer and Its Complexes with a Pre-miRNA Substrate

Cited by 65 publications

References 0 publications

Dicer's Helicase Domain: A Meeting Place for Regulatory Proteins

Dicer's Helicase Domain: A Meeting Place for Regulatory Proteins

Structure and function of Rnt1p: An alternative to RNAi for targeted RNA degradation

DICER1‐associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: Pathology, molecular genetics, and indications for molecular testing

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