Nucleolar organization, ribosomal DNA array stability, and acrocentric chromosome integrity are linked to telomere function.
Abstract
The short arms of the ten acrocentric human chromosomes share several repetitive DNAs,
including ribosomal RNA genes (rDNA). The rDNA arrays correspond to nucleolar organizing
regions that coalesce each cell cycle to form the nucleolus. Telomere disruption by
expressing a mutant version of telomere binding protein TRF2 (dnTRF2) causes non-random
acrocentric fusions, as well as large-scale nucleolar defects. The mechanisms responsible
for acrocentric chromosome sensitivity to dysfunctional telomeres are unclear. In
this study, we show that TRF2 normally associates with the nucleolus and rDNA. However,
when telomeres are crippled by dnTRF2 or RNAi knockdown of TRF2, gross nucleolar and
chromosomal changes occur. We used the controllable dnTRF2 system to precisely dissect
the timing and progression of nucleolar and chromosomal instability induced by telomere
dysfunction, demonstrating that nucleolar changes precede the DNA damage and morphological
changes that occur at acrocentric short arms. The rDNA repeat arrays on the short
arms decondense, and are coated by RNA polymerase I transcription binding factor UBF,
physically linking acrocentrics to one another as they become fusogenic. These results
highlight the importance of telomere function in nucleolar stability and structural
integrity of acrocentric chromosomes, particularly the rDNA arrays. Telomeric stress
is widely accepted to cause DNA damage at chromosome ends, but our findings suggest
that it also disrupts chromosome structure beyond the telomere region, specifically
within the rDNA arrays located on acrocentric chromosomes. These results have relevance
for Robertsonian translocation formation in humans and mechanisms by which acrocentric-acrocentric
fusions are promoted by DNA damage and repair.
Type
Journal articleSubject
Cell LineChromosomal Instability
DNA Damage
DNA Repair
DNA, Ribosomal
Gene Expression Regulation
Humans
Nucleolus Organizer Region
Pol1 Transcription Initiation Complex Proteins
Telomere
Telomeric Repeat Binding Protein 2
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https://hdl.handle.net/10161/9507Published Version (Please cite this version)
10.1371/journal.pone.0092432Publication Info
Stimpson, Kaitlin M; Sullivan, Lori L; Kuo, Molly E; & Sullivan, Beth A (2014). Nucleolar organization, ribosomal DNA array stability, and acrocentric chromosome
integrity are linked to telomere function. PLoS One, 9(3). pp. e92432. 10.1371/journal.pone.0092432. Retrieved from https://hdl.handle.net/10161/9507.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Beth Ann Sullivan
Professor of Molecular Genetics and Microbiology
Research in the Sullivan Lab is focused on chromosome organization, with a specific
emphasis on the genomics and epigenetics of the chromosomal locus called the centromere
and the formation and fate of chromosome abnormalities that are associated with birth
defects, reproductive abnormalities, and cancer. The centromere is a specialized chromosomal
site involved in chromosome architecture and movement, kinetochore function, heterochromatin
assembly, and sister chromatid cohesion.Our

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