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    Fusion of Inverted Repeats Leads to Formation of Dicentric Chromosomes that Cause Genome Instability in Budding Yeast

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    Author
    Kaochar, Salma
    Issue Date
    2010
    Keywords
    budding yeast
    checkpoint
    Dicentric chromosome
    faulty template switch
    Genome rearrangements
    Inverted repeats
    Advisor
    Weinert, Ted
    
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    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Embargo
    Embargo: Release after 5/3/2012
    Abstract
    Large-scale changes are common in genomes, and are often associated with pathological disorders. In the work presented in this dissertation, I provide insights into how inverted repeat sequences in budding yeast fuse during replication. Fusion leads to the formation of dicentric chromosomes, a translocation, and other chromosomal rearrangements.Using extensive genetics and some molecular analyses, I demonstrate that dicentric chromosomes are key intermediates in genome instability of a specific chromosome in budding yeast. I provide three pieces of evidence that is consistent with this conclusion. First, I detect a recombination fusion junction that is diagnostic of a dicentric chromosome (using a PCR technique). Second, I show a strong correlation between the amount of the dicentric fragment and the frequency of instability of the entire chromosome. Third, I demonstrate that a mutant known to stabilize dicentric chromosomes suppress instability. Based on these observations, I conclude that dicentric chromosomes are intermediates in causing genome instability in this system.Next, we demonstrate that fusion of inverted repeats is general. Both endogenous and synthetic nearby inverted repeats can fuse. Using genetics, I also show that many DNA repair and checkpoint pathways suppress fusion of nearby inverted repeats and genome instability. Based on our analysis, we propose a novel mechanism for fusion of inverted repeats that we term `faulty template switching.'Lastly, I discuss two genes that are necessary for fusion of nearby inverted repeats. I identified a mutant of the Exonuclease 1 (Exo1) and a mutant of anaphase inhibitor securin (Pds1) that suppress nearby inverted repeat fusion and genome instability. Studies of Exo1 and Pds1 provide us with insights into the molecular mechanisms of fusion.Our finding that nearby inverted repeats can fuse to form dicentric chromosomes that lead to genome instability may have great implications. The generality of this fusion reaction raises the possibility that dicentric chromosomes formed by inverted repeats can lead to genome instability in mammalian cells, and thereby contribute to a cancer phenotype.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Molecular & Cellular Biology
    Degree Grantor
    University of Arizona
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