The nature of telomere fusion and a definition of the critical telomere length in human cells

Genes Dev. 2007 Oct 1;21(19):2495-508. doi: 10.1101/gad.439107.

Abstract

The loss of telomere function can result in telomeric fusion events that lead to the types of genomic rearrangements, such as nonreciprocal translocations, that typify early-stage carcinogenesis. By using single-molecule approaches to characterize fusion events, we provide a functional definition of fusogenic telomeres in human cells. We show that approximately half of the fusion events contained no canonical telomere repeats at the fusion point; of those that did, the longest was 12.8 repeats. Furthermore, in addition to end-replication losses, human telomeres are subjected to large-scale deletion events that occur in the presence or absence of telomerase. Here we show that these telomeres are fusogenic, and thus despite the majority of telomeres being maintained at a stable length in normal human cells, a subset of stochastically shortened telomeres can potentially cause chromosomal instability. Telomere fusion was accompanied by the deletion of one or both telomeres extending several kilobases into the telomere-adjacent DNA, and microhomology was observed at the fusion points. This contrasted with telomere fusion that was observed following the experimental disruption of TRF2. The distinct error-prone mutational profile of fusion between critically shortened telomeres in human cells was reminiscent of Ku-independent microhomology-mediated end-joining.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line, Tumor
  • Cellular Senescence / genetics*
  • Chromosomal Instability / genetics*
  • Humans
  • Molecular Sequence Data
  • Mutagenesis, Insertional
  • Sequence Deletion
  • Tandem Repeat Sequences
  • Telomere / genetics
  • Telomere / metabolism*
  • Telomeric Repeat Binding Protein 2 / genetics

Substances

  • Telomeric Repeat Binding Protein 2