Homologous Recombination-Directed Mechanisms of Alternative Lengthening of Telomeres

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dc.contributor.advisorRoger A. Greenberg
dc.contributor.advisorMichael A. Lampson
dc.contributor.authorCho, Nam Woo
dc.date2023-05-17T15:53:27.000
dc.date.accessioned2023-05-22T16:42:54Z
dc.date.available2018-10-22T00:00:00Z
dc.date.copyright2016-11-29T00:00:00-08:00
dc.date.issued2015-01-01
dc.date.submitted2016-11-29T13:00:08-08:00
dc.description.abstractTelomere length maintenance is a requisite feature of cellular immortalization and a hallmark of human cancer. While most human cancers express telomerase activity, ∼10%-15% employ a recombination-dependent telomere maintenance pathway known as alternative lengthening of telomeres (ALT) that is characterized by multi-telomere clusters and associated promyelocytic leukemia protein bodies. However, the mechanisms that govern the lengthening process are poorly understood. Here, we show that a DNA double-strand break (DSB) response at ALT telomeres triggers long-range movement and clustering between chromosome termini, resulting in homology-directed telomere synthesis. Damaged telomeres initiate increased random surveillance of nuclear space before displaying rapid directional movement and association with recipient telomeres over micron-range distances. This phenomenon required Rad51 and the Hop2-Mnd1 heterodimer, which are essential for homologous chromosome synapsis during meiosis. Recruitment of Rad51 and Hop2 to damaged telomeres was dependent on ATR and Chk1 signaling. These findings implicate a specialized homology searching mechanism in ALT-dependent telomere maintenance and provide a molecular basis underlying the preference for recombination between nonsister telomeres during ALT.
dc.description.degreeDoctor of Philosophy (PhD)
dc.format.extent125 p.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://repository.upenn.edu/handle/20.500.14332/28489
dc.languageen
dc.legacy.articleid3441
dc.legacy.fulltexturlhttps://repository.upenn.edu/cgi/viewcontent.cgi?article=3441&context=edissertations&unstamped=1
dc.provenanceReceived from ProQuest
dc.relation.urlhttps://repository.upenn.edu/cgi/viewcontent.cgi?filename=0&article=3441&context=edissertations&type=additional
dc.relation.urlhttps://repository.upenn.edu/cgi/viewcontent.cgi?filename=1&article=3441&context=edissertations&type=additional
dc.relation.urlhttps://repository.upenn.edu/cgi/viewcontent.cgi?filename=2&article=3441&context=edissertations&type=additional
dc.relation.urlhttps://repository.upenn.edu/cgi/viewcontent.cgi?filename=3&article=3441&context=edissertations&type=additional
dc.relation.urlhttps://repository.upenn.edu/cgi/viewcontent.cgi?filename=4&article=3441&context=edissertations&type=additional
dc.relation.urlhttps://repository.upenn.edu/cgi/viewcontent.cgi?filename=5&article=3441&context=edissertations&type=additional
dc.relation.urlhttps://repository.upenn.edu/cgi/viewcontent.cgi?filename=6&article=3441&context=edissertations&type=additional
dc.rightsNam Woo Cho
dc.source.issue1655
dc.source.journalPublicly Accessible Penn Dissertations
dc.source.statuspublished
dc.subject.otherAlternative Lengthening of Telomeres
dc.subject.otherHomologous recombination
dc.subject.otherCell Biology
dc.subject.otherMolecular Biology
dc.titleHomologous Recombination-Directed Mechanisms of Alternative Lengthening of Telomeres
dc.typeDissertation/Thesis
digcom.contributor.authorisAuthorOfPublication|email:namwcho@mail.med.upenn.edu|institution:University of Pennsylvania|Cho, Nam Woo
digcom.date.embargo2018-10-22T00:00:00-07:00
digcom.identifieredissertations/1655
digcom.identifier.contextkey9424461
digcom.identifier.submissionpathedissertations/1655
digcom.typedissertation
dspace.entity.typePublication
relation.isAuthorOfPublicationd17f4d9c-0bd9-4468-b30f-669bb0a6ccda
relation.isAuthorOfPublication.latestForDiscoveryd17f4d9c-0bd9-4468-b30f-669bb0a6ccda
upenn.graduate.groupCell & Molecular Biology
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