Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes.

dc.contributor.author

Stimpson, Kaitlin M

dc.contributor.author

Song, Ihn Young

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Jauch, Anna

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Holtgreve-Grez, Heidi

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Hayden, Karen E

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Bridger, Joanna M

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Sullivan, Beth A

dc.coverage.spatial

United States

dc.date.accessioned

2011-06-21T17:31:21Z

dc.date.accessioned

2017-08-01T13:43:26Z

dc.date.available

2017-08-01T13:43:26Z

dc.date.issued

2010-08-12

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.description.version

Version of Record

dc.identifier

https://www.ncbi.nlm.nih.gov/pubmed/20711355

dc.identifier.eissn

1553-7404

dc.identifier.uri

https://hdl.handle.net/10161/15131

dc.language

eng

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en_US

dc.publisher

Public Library of Science (PLoS)

dc.relation.ispartof

PLoS Genet

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10.1371/journal.pgen.1001061

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Plos Genetics

dc.relation.replaces

http://hdl.handle.net/10161/4476

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10161/4476

dc.subject

Cell Line

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Centromere

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Chromosomes, Human

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DNA, Satellite

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Humans

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Telomere

dc.title

Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes.

dc.title.alternative
dc.type

Journal article

duke.contributor.orcid

Sullivan, Beth A|0000-0001-5216-4603

duke.date.pubdate

2010-8-0

duke.description.issue

8

duke.description.volume

6

pubs.author-url

https://www.ncbi.nlm.nih.gov/pubmed/20711355

pubs.begin-page

e1001061

pubs.issue

8

pubs.organisational-group

Basic Science Departments

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Duke

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Duke Cancer Institute

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Institutes and Centers

pubs.organisational-group

Molecular Genetics and Microbiology

pubs.organisational-group

School of Medicine

pubs.publication-status

Published online

pubs.volume

6

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