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dc.contributor.advisorLobachev, Kirill S.
dc.contributor.authorZhang, Yu
dc.date.accessioned2014-08-27T13:32:39Z
dc.date.available2014-08-28T05:30:05Z
dc.date.created2013-08
dc.date.issued2013-06-28
dc.date.submittedAugust 2013
dc.identifier.urihttp://hdl.handle.net/1853/52185
dc.description.abstractDNA repetitive sequences capable of adopting non-B DNA structures are a potent source of instability in eukaryotic genomes. They are strong inducers of chromosomal fragility and genome rearrangements that cause various hereditary diseases and cancers. In addition, a subset of repeats also has an ability to expand, which leads to more than 20 human genetic diseases that are collectively known as repeat expansion diseases. However, the mechanisms underlying the potential of these structure-prone motifs to break and expand are largely unknown. In this study, a systematic genome-wide screen was employed in yeast Saccharomyces cerevisiae to investigate the contributing factors of the instability of two representative non-B DNA-forming repeats: the triplex-adopting GAA/TTC tracts and the inverted repeats that can form hairpin and cruciform structures. The GAA/TTC screen revealed that DNA replication and transcription initiation are the two major pathways governing the GAA/TTC stability in yeast, as corresponding mutants strongly induce both fragility and large-scale expansions of the repeats. The inverted repeats screen and follow-up experiments revealed that both replication-dependent and -independent pathways are involved in maintaining the stability of palindromic sequences. We propose that similar mechanisms could operate in the human cells to mediate the deleterious metabolism of GAA and inverted repeats.
dc.format.mimetypeapplication/pdf
dc.language.isoen_US
dc.publisherGeorgia Institute of Technology
dc.subjectGAA/TTC repeats
dc.subjectPalindromic sequence
dc.subjectFragility
dc.subjectExpansion
dc.subjectInstability
dc.subjectReplication
dc.subjectTranscription
dc.subjectHomologous recombination
dc.titleMechanisms of chromosomal instability induced by unstable DNA repeats in yeast S.cerevisiae
dc.typeDissertation
dc.description.degreePh.D.
dc.contributor.departmentBiology
dc.embargo.terms2014-08-01
thesis.degree.levelDoctoral
dc.contributor.committeeMemberHammer, Brian
dc.contributor.committeeMemberRudd, Katie
dc.contributor.committeeMemberChernoff, Yuri
dc.contributor.committeeMemberStorici, Francesca
dc.date.updated2014-08-27T13:32:39Z


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