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  1. Article ; Online: Highly conserved s2m element of SARS-CoV-2 dimerizes via a kissing complex and interacts with host miRNA-1307-3p.

    Imperatore, Joshua A / Cunningham, Caylee L / Pellegrene, Kendy A / Brinson, Robert G / Marino, John P / Evanseck, Jeffrey D / Mihailescu, Mihaela Rita

    Nucleic acids research

    2022  Volume 50, Issue 2, Page(s) 1017–1032

    Abstract: The ongoing COVID-19 pandemic highlights the necessity for a more fundamental understanding of the coronavirus life cycle. The causative agent of the disease, SARS-CoV-2, is being studied extensively from a structural standpoint in order to gain insight ... ...

    Abstract The ongoing COVID-19 pandemic highlights the necessity for a more fundamental understanding of the coronavirus life cycle. The causative agent of the disease, SARS-CoV-2, is being studied extensively from a structural standpoint in order to gain insight into key molecular mechanisms required for its survival. Contained within the untranslated regions of the SARS-CoV-2 genome are various conserved stem-loop elements that are believed to function in RNA replication, viral protein translation, and discontinuous transcription. While the majority of these regions are variable in sequence, a 41-nucleotide s2m element within the genome 3' untranslated region is highly conserved among coronaviruses and three other viral families. In this study, we demonstrate that the SARS-CoV-2 s2m element dimerizes by forming an intermediate homodimeric kissing complex structure that is subsequently converted to a thermodynamically stable duplex conformation. This process is aided by the viral nucleocapsid protein, potentially indicating a role in mediating genome dimerization. Furthermore, we demonstrate that the s2m element interacts with multiple copies of host cellular microRNA (miRNA) 1307-3p. Taken together, our results highlight the potential significance of the dimer structures formed by the s2m element in key biological processes and implicate the motif as a possible therapeutic drug target for COVID-19 and other coronavirus-related diseases.
    MeSH term(s) 3' Untranslated Regions/genetics ; Base Sequence ; Binding Sites/genetics ; COVID-19/genetics ; COVID-19/metabolism ; COVID-19/virology ; Conserved Sequence/genetics ; Dimerization ; Genome, Viral/genetics ; Host-Pathogen Interactions/genetics ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Nucleic Acid Conformation ; Nucleotide Motifs/genetics ; Proton Magnetic Resonance Spectroscopy/methods ; RNA, Viral/chemistry ; RNA, Viral/genetics ; RNA, Viral/metabolism ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; SARS-CoV-2/physiology
    Chemical Substances 3' Untranslated Regions ; MIRN1307 microRNA, human ; MicroRNAs ; RNA, Viral
    Language English
    Publishing date 2022-02-07
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkab1226
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  2. Article ; Online: Characterization of a G-Quadruplex Structure in Pre-miRNA-1229 and in Its Alzheimer's Disease-Associated Variant rs2291418: Implications for miRNA-1229 Maturation.

    Imperatore, Joshua A / Then, McKenna L / McDougal, Keefe B / Mihailescu, Mihaela Rita

    International journal of molecular sciences

    2020  Volume 21, Issue 3

    Abstract: Alzheimer's disease (AD), the most common age-related neurodegenerative disease, is associated with various forms of cognitive and functional impairment that worsen with disease progression. AD is typically characterized as a protein misfolding disease, ... ...

    Abstract Alzheimer's disease (AD), the most common age-related neurodegenerative disease, is associated with various forms of cognitive and functional impairment that worsen with disease progression. AD is typically characterized as a protein misfolding disease, in which abnormal plaques form due to accumulation of tau and β-amyloid (Aβ) proteins. An assortment of proteins is responsible for the processing and trafficking of Aβ, including sortilin-related receptor 1 (SORL1). Recently, a genome-wide association study of microRNA-related variants found that a single nucleotide polymorphism (SNP) rs2291418 within premature microRNA-1229 (pre-miRNA-1229) is significantly associated with AD. Moreover, the levels of the mature miRNA-1229-3p, which has been shown to regulate the SORL1 translation, are increased in the rs2291418 pre-miRNA-1229 variant. In this study we used various biophysical techniques to show that pre-miRNA-1229 forms a G-quadruplex secondary structure that coexists in equilibrium with the canonical hairpin structure, potentially controlling the production of the mature miR-1229-3p, and furthermore, that the AD-associated SNP rs2291418 pre-miR-1229 changes the equilibrium between these structures. Thus, the G-quadruplex structure we identified within pre-miRNA-1229 could potentially act as a novel therapeutic target in AD.
    MeSH term(s) Alzheimer Disease ; Amyloid beta-Peptides/genetics ; Amyloid beta-Peptides/metabolism ; G-Quadruplexes ; Humans ; MicroRNAs/chemistry ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Nucleic Acid Conformation ; Polymorphism, Single Nucleotide
    Chemical Substances Amyloid beta-Peptides ; MIRN1229 microRNA, human ; MicroRNAs
    Language English
    Publishing date 2020-01-24
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms21030767
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  3. Article ; Online: Characterization of a G-Quadruplex Structure in Pre-miRNA-1229 and in Its Alzheimer’s Disease-Associated Variant rs2291418

    Joshua A. Imperatore / McKenna L. Then / Keefe B. McDougal / Mihaela Rita Mihailescu

    International Journal of Molecular Sciences, Vol 21, Iss 3, p

    Implications for miRNA-1229 Maturation

    2020  Volume 767

    Abstract: Alzheimer’s disease (AD), the most common age-related neurodegenerative disease, is associated with various forms of cognitive and functional impairment that worsen with disease progression. AD is typically characterized as a protein misfolding disease, ... ...

    Abstract Alzheimer’s disease (AD), the most common age-related neurodegenerative disease, is associated with various forms of cognitive and functional impairment that worsen with disease progression. AD is typically characterized as a protein misfolding disease, in which abnormal plaques form due to accumulation of tau and β-amyloid (Aβ) proteins. An assortment of proteins is responsible for the processing and trafficking of Aβ, including sortilin-related receptor 1 (SORL1). Recently, a genome-wide association study of microRNA-related variants found that a single nucleotide polymorphism (SNP) rs2291418 within premature microRNA-1229 (pre-miRNA-1229) is significantly associated with AD. Moreover, the levels of the mature miRNA-1229-3p, which has been shown to regulate the SORL1 translation, are increased in the rs2291418 pre-miRNA-1229 variant. In this study we used various biophysical techniques to show that pre-miRNA-1229 forms a G-quadruplex secondary structure that coexists in equilibrium with the canonical hairpin structure, potentially controlling the production of the mature miR-1229-3p, and furthermore, that the AD-associated SNP rs2291418 pre-miR-1229 changes the equilibrium between these structures. Thus, the G-quadruplex structure we identified within pre-miRNA-1229 could potentially act as a novel therapeutic target in AD.
    Keywords rna g-quadruplex ; pre-mirna-1229 ; alzheimer’s disease ; rs2291418 ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Structural, Dynamical, and Entropic Differences between SARS-CoV and SARS-CoV-2 s2m Elements Using Molecular Dynamics Simulations.

    Kensinger, Adam H / Makowski, Joseph A / Pellegrene, Kendy A / Imperatore, Joshua A / Cunningham, Caylee L / Frye, Caleb J / Lackey, Patrick E / Mihailescu, Mihaela Rita / Evanseck, Jeffrey D

    ACS physical chemistry Au

    2022  Volume 3, Issue 1, Page(s) 30–43

    Abstract: The functional role of the highly conserved stem-loop II motif (s2m) in SARS-CoV and SARS-CoV-2 in the viral lifecycle remains enigmatic and an intense area of research. Structure and dynamics of the s2m are key to establishing a structure-function ... ...

    Abstract The functional role of the highly conserved stem-loop II motif (s2m) in SARS-CoV and SARS-CoV-2 in the viral lifecycle remains enigmatic and an intense area of research. Structure and dynamics of the s2m are key to establishing a structure-function connection, yet a full set of atomistic resolution coordinates is not available for SARS-CoV-2 s2m. Our work constructs three-dimensional coordinates consistent with NMR solution phase data for SARS-CoV-2 s2m and provides a comparative analysis with its counterpart SARS-CoV s2m. We employed initial coordinates based on PDB ID 1XJR for SARS-CoV s2m and two models for SARS-CoV-2 s2m: one based on 1XJR in which we introduced the mutations present in SARS-CoV-2 s2m and the second based on the available SARS-CoV-2 NMR NOE data supplemented with knowledge-based methods. For each of the three systems, 3.5 μs molecular dynamics simulations were used to sample the structure and dynamics, and principal component analysis (PCA) reduced the ensembles to hierarchal conformational substates for detailed analysis. Dilute solution simulations of SARS-CoV s2m demonstrate that the GNRA-like terminal pentaloop is rigidly defined by base stacking uniquely positioned for possible kissing dimer formation. However, the SARS-CoV-2 s2m simulation did not retain the reported crystallographic SARS-CoV motifs and the terminal loop expands to a highly dynamic "nonaloop." Increased flexibility and structural disorganization are observed for the larger terminal loop, where an entropic penalty is computed to explain the experimentally observed reduction in kissing complex formation. Overall, both SARS-CoV and SARS-CoV-2 s2m elements have a similarly pronounced L-shape due to different motif interactions. Our study establishes the atomistic three-dimensional structure and uncovers dynamic differences that arise from s2m sequence changes, which sets the stage for the interrogation of different mechanistic pathways of suspected biological function.
    Language English
    Publishing date 2022-10-04
    Publishing country United States
    Document type Journal Article
    ISSN 2694-2445
    ISSN (online) 2694-2445
    DOI 10.1021/acsphyschemau.2c00032
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  5. Article: FUS Recognizes G Quadruplex Structures Within Neuronal mRNAs.

    Imperatore, Joshua A / McAninch, Damian S / Valdez-Sinon, Arielle N / Bassell, Gary J / Mihailescu, Mihaela Rita

    Frontiers in molecular biosciences

    2020  Volume 7, Page(s) 6

    Abstract: Fused in sarcoma (FUS), identified as the heterogeneous nuclear ribonuclear protein P2, is expressed in neuronal and non-neuronal tissue, and among other functions, has been implicated in messenger RNA (mRNA) transport and possibly local translation ... ...

    Abstract Fused in sarcoma (FUS), identified as the heterogeneous nuclear ribonuclear protein P2, is expressed in neuronal and non-neuronal tissue, and among other functions, has been implicated in messenger RNA (mRNA) transport and possibly local translation regulation. Although FUS is mainly localized to the nucleus, in the neurons FUS has also been shown to localize to the post-synaptic density, as well as to the pre-synapse. Additionally, the FUS deletion in cultured hippocampal cells results in abnormal spine and dendrite morphology. Thus, FUS may play a role in synaptic function regulation, mRNA localization, and local translation. Many dendritic mRNAs have been shown to form G quadruplex structures in their 3'-untranslated region (3'-UTR). Since FUS contains three arginine-glycine-glycine (RGG) boxes, an RNA binding domain shown to bind with high affinity and specificity to RNA G quadruplex structures, in this study we hypothesized that FUS recognizes these structural elements in its neuronal mRNA targets. Two neuronal mRNAs found in the pre- and post-synapse are the post-synaptic density protein 95 (PSD-95) and Shank1 mRNAs, which encode for proteins involved in synaptic plasticity, maintenance, and function. These mRNAs have been shown to form 3'-UTR G quadruplex structures and were also enriched in FUS hydrogels. In this study, we used native gel electrophoresis and steady-state fluorescence spectroscopy to demonstrate specific nanomolar binding of the FUS C-terminal RGG box and of full-length FUS to the RNA G quadruplex structures formed in the 3'-UTR of PSD-95 and Shank1a mRNAs. These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.
    Language English
    Publishing date 2020-02-07
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2814330-9
    ISSN 2296-889X
    ISSN 2296-889X
    DOI 10.3389/fmolb.2020.00006
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  6. Article ; Online: SARS-CoV-2 highly conserved s2m element dimerizes via a kissing complex and interacts with host miRNA-1307-3p

    Imperatore, Joshua A. / Cunningham, Caylee L / Pellegrene, Kendy A. / Brinson, Robert G. / Marino, John P. / Evanseck, Jeffrey D. / Mihailescu, Mihaela Rita

    bioRxiv

    Abstract: The ongoing COVID-19 pandemic highlights the necessity for a more fundamental understanding of the coronavirus life cycle. The causative agent of the disease, SARS-CoV-2, is being studied extensively from a structural standpoint in order to gain insight ... ...

    Abstract The ongoing COVID-19 pandemic highlights the necessity for a more fundamental understanding of the coronavirus life cycle. The causative agent of the disease, SARS-CoV-2, is being studied extensively from a structural standpoint in order to gain insight into key molecular mechanisms required for its survival. Contained within the untranslated regions of the SARS-CoV-2 genome are various conserved stem-loop elements that are believed to function in RNA replication, viral protein translation, and discontinuous transcription. While the majority of these regions are variable in sequence, a 41-nucleotide s2m element within the 3- UTR is highly conserved among coronaviruses and three other viral families. In this study, we demonstrate that the s2m element of SARS-CoV-2 dimerizes by forming an intermediate homodimeric kissing complex structure that is subsequently converted to a thermodynamically stable duplex conformation. This process is aided by the viral nucleocapsid protein, potentially indicating a role in mediating genome dimerization. Furthermore, we demonstrate that the s2m element interacts with multiple copies of host cellular miRNA-1307-3p. Taken together, our results highlight the potential significance of the dimer structures formed by the s2m element in key biological processes and implicate the motif as a possible therapeutic drug target for COVID-19 and other coronavirus-related diseases.
    Keywords covid19
    Language English
    Publishing date 2020-12-29
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2020.12.29.424733
    Database COVID19

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  7. Article ; Online: B-cell differentiation in EBV-positive Burkitt lymphoma is impaired at posttranscriptional level by miRNA-altered expression.

    Leucci, Eleonora / Onnis, Anna / Cocco, Mario / De Falco, Giulia / Imperatore, Francesco / Giuseppina, Antonicelli / Costanzo, Valentina / Cerino, Giovanna / Mannucci, Susanna / Cantisani, Rocco / Nyagol, Joshua / Mwanda, Walter / Iriso, Robert / Owang, Martin / Schurfeld, Karin / Bellan, Cristiana / Lazzi, Stefano / Leoncini, Lorenzo

    International journal of cancer

    2010  Volume 126, Issue 6, Page(s) 1316–1326

    Abstract: Endemic, sporadic and HIV-associated Burkitt lymphoma (BL) all have a B-cell phenotype and a MYC translocation, but a variable association with the Epstein-Barr virus (EBV). However, there is still no satisfactory explanation of how EBV participates in ... ...

    Abstract Endemic, sporadic and HIV-associated Burkitt lymphoma (BL) all have a B-cell phenotype and a MYC translocation, but a variable association with the Epstein-Barr virus (EBV). However, there is still no satisfactory explanation of how EBV participates in the pathogenesis of BL. A recent investigation suggested that EBV-positive and EBV-negative BL have different cells of origin. In particular, according to immunoglobulin gene mutation analysis, EBV-negative BLs may originate from early centroblasts, whereas EBV-positive BLs seem to arise from postgerminal center B cells or memory B cells. The appearance of a germinal center phenotype in EBV-positive cells might thus derive from a block in B-cell differentiation. The exit from the germinal center involves a complex series of events, which require the activation of BLIMP-1, and the consequent downregulation of several target genes. Here, we investigated the expression of specific miRNAs predicted to be involved in B-cell differentiation and found that hsa-miR-127 is differentially expressed between EBV-positive and EBV-negative BLs. In particular, it was strongly upregulated only in EBV-positive BL samples, whereas EBV-negative cases showed levels of expression similar to normal controls, including microdissected germinal centers (GC) cells. In addition, we found evidence that hsa-miR-127 is involved in B-cell differentiation process through posttranscriptional regulation of BLIMP1 and XBP1. The overexpression of this miRNA may thus represent a key event in the lymphomagenesis of EBV positive BL, by blocking the B-cell differentiation process.
    MeSH term(s) Adolescent ; Adult ; B-Lymphocytes/metabolism ; B-Lymphocytes/pathology ; B-Lymphocytes/virology ; Blotting, Western ; Burkitt Lymphoma/genetics ; Burkitt Lymphoma/metabolism ; Burkitt Lymphoma/pathology ; Cell Differentiation ; Cell Line, Tumor ; Child ; Child, Preschool ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Herpesvirus 4, Human/growth & development ; Humans ; Male ; MicroRNAs/genetics ; Middle Aged ; Positive Regulatory Domain I-Binding Factor 1 ; RNA Processing, Post-Transcriptional ; Regulatory Factor X Transcription Factors ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factors/genetics ; Transcription Factors/metabolism ; X-Box Binding Protein 1 ; Young Adult
    Chemical Substances DNA-Binding Proteins ; MIRN127 microRNA, human ; MicroRNAs ; Regulatory Factor X Transcription Factors ; Repressor Proteins ; Transcription Factors ; X-Box Binding Protein 1 ; XBP1 protein, human ; PRDM1 protein, human (138415-26-6) ; Positive Regulatory Domain I-Binding Factor 1 (EC 2.1.1.-)
    Language English
    Publishing date 2010-03-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218257-9
    ISSN 1097-0215 ; 0020-7136
    ISSN (online) 1097-0215
    ISSN 0020-7136
    DOI 10.1002/ijc.24655
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    Zs.MO 576: Show issues

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