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  1. Article ; Online: Nuclear Pre-snRNA Export Is an Essential Quality Assurance Mechanism for Functional Spliceosomes

    Daniel Becker / Anna Greta Hirsch / Lysann Bender / Thomas Lingner / Gabriela Salinas / Heike Krebber

    Cell Reports, Vol 27, Iss 11, Pp 3199-3214.e

    2019  Volume 3

    Abstract: Summary: Removal of introns from pre-mRNAs is an essential step in eukaryotic gene expression, mediated by spliceosomes that contain snRNAs as key components. Although snRNAs are transcribed in the nucleus and function in the same compartment, all except ...

    Abstract Summary: Removal of introns from pre-mRNAs is an essential step in eukaryotic gene expression, mediated by spliceosomes that contain snRNAs as key components. Although snRNAs are transcribed in the nucleus and function in the same compartment, all except U6 shuttle to the cytoplasm. Surprisingly, the physiological relevance for shuttling is unclear, in particular because the snRNAs in Saccharomyces cerevisiae were reported to remain nuclear. Here, we show that all yeast pre-snRNAs including U6 undergo a stepwise maturation process after nuclear export by Mex67 and Xpo1. Sm- and Lsm-ring attachment occurs in the cytoplasm and is important for the snRNA re-import, mediated by Cse1 and Mtr10. Finally, nuclear pre-snRNA cleavage and trimethylation of the 5′-cap finalizes shuttling. Importantly, preventing pre-snRNAs from being exported or processed results in faulty spliceosome assembly and subsequent genome-wide splicing defects. Thus, pre-snRNA export is obligatory for functional splicing and resembles an essential evolutionarily conserved quality assurance step. : Becker et al. show snRNA maturation in yeast involves nuclear export and re-import mediated by Mex67-Mtr2 and Xpo1/Crm1 and by Mtr10 and Cse1, respectively. They propose a model for obligatory shuttling in eukaryotes by showing spliceosomes assemble with immature snRNAs when export is prevented, resulting in defective spliceosomes and genome-wide splicing defects. Keywords: snRNA, splicing, mRNA, U6, Mex67, Xpo1/Crm1, Mtr10, Cse1, RNA processing, RNA quality control, ncRNA export
    Keywords Biology (General) ; QH301-705.5
    Subject code 381
    Language English
    Publishing date 2019-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Nuclear Pre-snRNA Export Is an Essential Quality Assurance Mechanism for Functional Spliceosomes.

    Becker, Daniel / Hirsch, Anna Greta / Bender, Lysann / Lingner, Thomas / Salinas, Gabriela / Krebber, Heike

    Cell reports

    2019  Volume 27, Issue 11, Page(s) 3199–3214.e3

    Abstract: Removal of introns from pre-mRNAs is an essential step in eukaryotic gene expression, mediated by spliceosomes that contain snRNAs as key components. Although snRNAs are transcribed in the nucleus and function in the same compartment, all except U6 ... ...

    Abstract Removal of introns from pre-mRNAs is an essential step in eukaryotic gene expression, mediated by spliceosomes that contain snRNAs as key components. Although snRNAs are transcribed in the nucleus and function in the same compartment, all except U6 shuttle to the cytoplasm. Surprisingly, the physiological relevance for shuttling is unclear, in particular because the snRNAs in Saccharomyces cerevisiae were reported to remain nuclear. Here, we show that all yeast pre-snRNAs including U6 undergo a stepwise maturation process after nuclear export by Mex67 and Xpo1. Sm- and Lsm-ring attachment occurs in the cytoplasm and is important for the snRNA re-import, mediated by Cse1 and Mtr10. Finally, nuclear pre-snRNA cleavage and trimethylation of the 5'-cap finalizes shuttling. Importantly, preventing pre-snRNAs from being exported or processed results in faulty spliceosome assembly and subsequent genome-wide splicing defects. Thus, pre-snRNA export is obligatory for functional splicing and resembles an essential evolutionarily conserved quality assurance step.
    MeSH term(s) Karyopherins/genetics ; Karyopherins/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Nucleocytoplasmic Transport Proteins/genetics ; Nucleocytoplasmic Transport Proteins/metabolism ; RNA Transport ; RNA, Small Nuclear/genetics ; RNA, Small Nuclear/metabolism ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Spliceosomes/metabolism ; Exportin 1 Protein
    Chemical Substances CSE1 protein, S cerevisiae ; Karyopherins ; MEX67 protein, S cerevisiae ; MTR10 protein, S cerevisiae ; Nuclear Proteins ; Nucleocytoplasmic Transport Proteins ; RNA, Small Nuclear ; RNA-Binding Proteins ; Receptors, Cytoplasmic and Nuclear ; Saccharomyces cerevisiae Proteins ; U6 small nuclear RNA
    Language English
    Publishing date 2019-06-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2019.05.031
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Book ; Online ; Thesis: Charakterisierung des mRNA-Exportweges bei zellulärem Stress in Saccharomyces cerevisiae

    Bender, Lysann [Verfasser] / Krebber, Heike [Akademischer Betreuer] [Gutachter] / Braus, Gerhard [Gutachter]

    2016  

    Author's details Lysann Bender ; Gutachter: Heike Krebber, Gerhard Braus ; Betreuer: Heike Krebber
    Keywords Biowissenschaften, Biologie ; Life Science, Biology
    Subject code sg570
    Language German
    Publisher Niedersächsische Staats- und Universitätsbibliothek Göttingen
    Publishing place Göttingen
    Document type Book ; Online ; Thesis
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  4. Article: Factor XII-Driven Inflammatory Reactions with Implications for Anaphylaxis.

    Bender, Lysann / Weidmann, Henri / Rose-John, Stefan / Renné, Thomas / Long, Andy T

    Frontiers in immunology

    2017  Volume 8, Page(s) 1115

    Abstract: Anaphylaxis is a life-threatening allergic reaction. It is triggered by the release of pro-inflammatory cytokines and mediators from mast cells and basophils in response to immunologic or non-immunologic mechanisms. Mediators that are released upon mast ... ...

    Abstract Anaphylaxis is a life-threatening allergic reaction. It is triggered by the release of pro-inflammatory cytokines and mediators from mast cells and basophils in response to immunologic or non-immunologic mechanisms. Mediators that are released upon mast cell activation include the highly sulfated polysaccharide and inorganic polymer heparin and polyphosphate (polyP), respectively. Heparin and polyP supply a negative surface for factor XII (FXII) activation, a serine protease that drives contact system-mediated coagulation and inflammation. Activation of the FXII substrate plasma kallikrein leads to further activation of zymogen FXII and triggers the pro-inflammatory kallikrein-kinin system that results in the release of the mediator bradykinin (BK). The severity of anaphylaxis is correlated with the intensity of contact system activation, the magnitude of mast cell activation, and BK formation. The main inhibitor of the complement system, C1 esterase inhibitor, potently interferes with FXII activity, indicating a meaningful cross-link between complement and kallikrein-kinin systems. Deficiency in a functional C1 esterase inhibitor leads to a severe swelling disorder called hereditary angioedema (HAE). The significance of FXII in these disorders highlights the importance of studying how these processes are integrated and can be therapeutically targeted. In this review, we focus on how FXII integrates with inflammation and the complement system to cause anaphylaxis and HAE as well as highlight current diagnosis and treatments of BK-related diseases.
    Language English
    Publishing date 2017-09-15
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2017.01115
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: mRNA quality control is bypassed for immediate export of stress-responsive transcripts.

    Zander, Gesa / Hackmann, Alexandra / Bender, Lysann / Becker, Daniel / Lingner, Thomas / Salinas, Gabriela / Krebber, Heike

    Nature

    2016  Volume 540, Issue 7634, Page(s) 593–596

    Abstract: Cells grow well only in a narrow range of physiological conditions. Surviving extreme conditions requires the instantaneous expression of chaperones that help to overcome stressful situations. To ensure the preferential synthesis of these heat-shock ... ...

    Abstract Cells grow well only in a narrow range of physiological conditions. Surviving extreme conditions requires the instantaneous expression of chaperones that help to overcome stressful situations. To ensure the preferential synthesis of these heat-shock proteins, cells inhibit transcription, pre-mRNA processing and nuclear export of non-heat-shock transcripts, while stress-specific mRNAs are exclusively exported and translated. How cells manage the selective retention of regular transcripts and the simultaneous rapid export of heat-shock mRNAs is largely unknown. In Saccharomyces cerevisiae, the shuttling RNA adaptor proteins Npl3, Gbp2, Hrb1 and Nab2 are loaded co-transcriptionally onto growing pre-mRNAs. For nuclear export, they recruit the export-receptor heterodimer Mex67-Mtr2 (TAP-p15 in humans). Here we show that cellular stress induces the dissociation of Mex67 and its adaptor proteins from regular mRNAs to prevent general mRNA export. At the same time, heat-shock mRNAs are rapidly exported in association with Mex67, without the need for adapters. The immediate co-transcriptional loading of Mex67 onto heat-shock mRNAs involves Hsf1, a heat-shock transcription factor that binds to heat-shock-promoter elements in stress-responsive genes. An important difference between the export modes is that adaptor-protein-bound mRNAs undergo quality control, whereas stress-specific transcripts do not. In fact, regular mRNAs are converted into uncontrolled stress-responsive transcripts if expressed under the control of a heat-shock promoter, suggesting that whether an mRNA undergoes quality control is encrypted therein. Under normal conditions, Mex67 adaptor proteins are recruited for RNA surveillance, with only quality-controlled mRNAs allowed to associate with Mex67 and leave the nucleus. Thus, at the cost of error-free mRNA formation, heat-shock mRNAs are exported and translated without delay, allowing cells to survive extreme situations.
    Language English
    Publishing date 2016-12-12
    Publishing country England
    Document type Journal Article
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/nature20572
    Database MEDical Literature Analysis and Retrieval System OnLINE

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