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dc.contributor.author Stimpson, KM
dc.contributor.author Song, IY
dc.contributor.author Jauch, A
dc.contributor.author Holtgreve-Grez, H
dc.contributor.author Hayden, KE
dc.contributor.author Bridger, JM
dc.contributor.author Sullivan, BA
dc.coverage.spatial United States
dc.date.accessioned 2011-06-21T17:31:21Z
dc.date.issued 2010-08-12
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/20711355
dc.identifier.citation PLoS Genet, 2010, 6 (8)
dc.identifier.uri http://hdl.handle.net/10161/4476
dc.description.abstract Genome rearrangement often produces chromosomes with two centromeres (dicentrics) that are inherently unstable because of bridge formation and breakage during cell division. However, mammalian dicentrics, and particularly those in humans, can be quite stable, usually because one centromere is functionally silenced. Molecular mechanisms of centromere inactivation are poorly understood since there are few systems to experimentally create dicentric human chromosomes. Here, we describe a human cell culture model that enriches for de novo dicentrics. We demonstrate that transient disruption of human telomere structure non-randomly produces dicentric fusions involving acrocentric chromosomes. The induced dicentrics vary in structure near fusion breakpoints and like naturally-occurring dicentrics, exhibit various inter-centromeric distances. Many functional dicentrics persist for months after formation. Even those with distantly spaced centromeres remain functionally dicentric for 20 cell generations. Other dicentrics within the population reflect centromere inactivation. In some cases, centromere inactivation occurs by an apparently epigenetic mechanism. In other dicentrics, the size of the alpha-satellite DNA array associated with CENP-A is reduced compared to the same array before dicentric formation. Extra-chromosomal fragments that contained CENP-A often appear in the same cells as dicentrics. Some of these fragments are derived from the same alpha-satellite DNA array as inactivated centromeres. Our results indicate that dicentric human chromosomes undergo alternative fates after formation. Many retain two active centromeres and are stable through multiple cell divisions. Others undergo centromere inactivation. This event occurs within a broad temporal window and can involve deletion of chromatin that marks the locus as a site for CENP-A maintenance/replenishment.
dc.language ENG
dc.language.iso en_US en_US
dc.relation.ispartof PLoS Genet
dc.relation.isversionof 10.1371/journal.pgen.1001061
dc.subject Cell Line
dc.subject Centromere
dc.subject Chromosomes, Human
dc.subject DNA, Satellite
dc.subject Humans
dc.subject Telomere
dc.title Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US
duke.date.pubdate 2010-8-0 en_US
duke.description.endpage e1001061 en_US
duke.description.issue 8 en_US
duke.description.startpage e1001061 en_US
duke.description.volume 6 en_US
dc.relation.journal Plos Genetics en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/20711355
pubs.issue 8
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Molecular Genetics and Microbiology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.publication-status Published online
pubs.volume 6
dc.identifier.eissn 1553-7404

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