The terminal telomeric DNA sequence determines the mechanism of dysfunctional telomere fusion

Bradley A. Stohr, Lifeng Xu, Elizabeth H. Blackburn

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Mammalian telomeres consist of tandem DNA repeats that bind protective protein factors collectively termed shelterins. Telomere disruption typically results in genome instability induced by telomere fusions. The mechanism of telomere fusion varies depending on the means of telomere disruption. Here, we investigate telomere fusions caused by overexpression of mutant telomerases that add mutated telomeric repeats, thereby compromising shelterin binding to telomeric termini. While all mutant telomeric sequences tested induced heterodicentric chromosome fusions in ATM-competent cells, only those mutant repeat sequences with significant self complementarity induced ATM-independent sister chromatid and isodicentric chromosome fusions. Thus, once a telomere becomes dysfunctional, the terminal telomeric sequence itself determines the fate of that telomere. These results suggest that annealing of self-complementary DNA sequence engages an alternative telomere fusion pathway in human cells, and provide one explanation for the conspicuous lack of self complementarity in the majority of known naturally occurring eukaryotic telomeric sequences.

Original languageEnglish (US)
Pages (from-to)307-314
Number of pages8
JournalMolecular Cell
Volume39
Issue number2
DOIs
StatePublished - Jul 2010

Keywords

  • DNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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