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    MECHANISM AND FUNCTION OF SPLICEOSOMAL CLEAVAGE IN FISSION YEAST

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    KANNAN_ku_0099D_12901_DATA_1.pdf (15.52Mb)
    Issue Date
    2013-08-31
    Author
    Kannan, Ram
    Publisher
    University of Kansas
    Format
    122 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Molecular & Integrative Physiology
    Rights
    This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
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    Abstract
    Telomerase is the ribonucleoprotein complex that replenishes lost DNA sequences at the ends of chromosomes. At its core, telomerase consists of an RNA subunit (TERC) that provides the template and a catalytic protein component (TERT). Insufficient telomerase activity leads to various disorders like dyskeratosis congenita, aplastic anemia and idiopathic pulmonary fibrosis. How different mutations in the same gene lead to disparate symptoms and disorders is not clear. The overall objective of my project is to understand the biogenesis of telomerase in the genetically tractable eukaryote S. pombe, whose telomere maintenance machinery closely resembles that of humans. Our laboratory has previously shown that the mature 3' end of S. pombe telomerase RNA (TER1) is generated by the first step of spliceosomal splicing. The cis- and trans- acting factors that distinguish the single step spliceosomal cleavage in TER1 from the two-step splicing reaction that removes introns in other genes are being investigated. We now demonstrate that a strong branch site (BS), a long distance to the 3' splice site (SS) and a weak polypyrimidine tract (Py) tract act synergistically to attenuate the transition from the first to the second step of splicing. The observation that a strong BS antagonizes the second step of splicing in the context of TER1 suggests that the BS-U2 snRNA interactions are disrupted after the first step and thus earlier than previously thought. The slow transition from first to second step triggers the Prp22 DExD/H-box helicase- dependent rejection of the cleaved products and Prp43-dependent discard of the splicing intermediates. Related to this work, we have established that the spliceosome generates the 3' ends of telomerase RNA in S. cryophilus and S. octosporus albeit via a different mechanism involving U6 snRNA hyperstabilization at the 5'ss. Our findings explain how the spliceosome can function in 3' end processing and provide new insights into the mechanism of splicing.
    URI
    http://hdl.handle.net/1808/14850
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    • Dissertations [4454]
    • Molecular Biosciences Dissertations and Theses [270]

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    KU Libraries
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    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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