Interchromosomal homology searches drive directional ALT telomere movement and synapsis

Cell. 2014 Sep 25;159(1):108-121. doi: 10.1016/j.cell.2014.08.030.


Telomere length maintenance is a requisite feature of cellular immortalization and a hallmark of human cancer. While most human cancers express telomerase activity, ∼10%-15% employ a recombination-dependent telomere maintenance pathway known as alternative lengthening of telomeres (ALT) that is characterized by multitelomere clusters and associated promyelocytic leukemia protein bodies. Here, we show that a DNA double-strand break (DSB) response at ALT telomeres triggers long-range movement and clustering between chromosome termini, resulting in homology-directed telomere synthesis. Damaged telomeres initiate increased random surveillance of nuclear space before displaying rapid directional movement and association with recipient telomeres over micron-range distances. This phenomenon required Rad51 and the Hop2-Mnd1 heterodimer, which are essential for homologous chromosome synapsis during meiosis. These findings implicate a specialized homology searching mechanism in ALT-dependent telomere maintenance and provide a molecular basis underlying the preference for recombination between nonsister telomeres during ALT.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Chromatin / metabolism
  • Chromosome Pairing*
  • DNA Breaks, Double-Stranded
  • Homologous Recombination
  • Humans
  • Nuclear Proteins / metabolism
  • Recombination, Genetic*
  • Site-Specific DNA-Methyltransferase (Adenine-Specific) / metabolism
  • Telomere / metabolism*
  • Telomeric Repeat Binding Protein 1 / metabolism
  • Trans-Activators / metabolism


  • Cell Cycle Proteins
  • Chromatin
  • MND1 protein, human
  • Nuclear Proteins
  • PSMC3IP protein, human
  • Telomeric Repeat Binding Protein 1
  • Trans-Activators
  • DNA modification methylase FokI
  • Site-Specific DNA-Methyltransferase (Adenine-Specific)