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

Publication ,  Journal Article
Stimpson, KM; Song, IY; Jauch, A; Holtgreve-Grez, H; Hayden, KE; Bridger, JM; Sullivan, BA
Published in: PLoS Genet
August 12, 2010

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.

Duke Scholars

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

August 12, 2010

Volume

6

Issue

8

Location

United States

Related Subject Headings

  • Telomere
  • Humans
  • Developmental Biology
  • DNA, Satellite
  • Chromosomes, Human
  • Centromere
  • Cell Line
  • 3105 Genetics
  • 0604 Genetics
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Stimpson, K. M., Song, I. Y., Jauch, A., Holtgreve-Grez, H., Hayden, K. E., Bridger, J. M., & Sullivan, B. A. (2010). Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes. PLoS Genet, 6(8). https://doi.org/10.1371/journal.pgen.1001061
Stimpson, Kaitlin M., Ihn Young Song, Anna Jauch, Heidi Holtgreve-Grez, Karen E. Hayden, Joanna M. Bridger, and Beth A. Sullivan. “Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes.PLoS Genet 6, no. 8 (August 12, 2010). https://doi.org/10.1371/journal.pgen.1001061.
Stimpson KM, Song IY, Jauch A, Holtgreve-Grez H, Hayden KE, Bridger JM, et al. Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes. PLoS Genet. 2010 Aug 12;6(8).
Stimpson, Kaitlin M., et al. “Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes.PLoS Genet, vol. 6, no. 8, Aug. 2010. Pubmed, doi:10.1371/journal.pgen.1001061.
Stimpson KM, Song IY, Jauch A, Holtgreve-Grez H, Hayden KE, Bridger JM, Sullivan BA. Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes. PLoS Genet. 2010 Aug 12;6(8).

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

August 12, 2010

Volume

6

Issue

8

Location

United States

Related Subject Headings

  • Telomere
  • Humans
  • Developmental Biology
  • DNA, Satellite
  • Chromosomes, Human
  • Centromere
  • Cell Line
  • 3105 Genetics
  • 0604 Genetics