TRF2 interaction with Ku heterotetramerization interface gives insight into c-NHEJ prevention at human telomeres

Cell Rep. 2013 Oct 17;5(1):194-206. doi: 10.1016/j.celrep.2013.08.040. Epub 2013 Oct 3.


Telomeres are protected from nonhomologous end-joining (NHEJ) to avoid deleterious chromosome fusions, yet they associate with the Ku heterodimer that is principal in the classical NHEJ (c-NHEJ) pathway. T-loops have been proposed to inhibit Ku's association with telomeric ends, thus inhibiting c-NHEJ; however, deficiencies in the t-loop model suggest additional mechanisms are in effect. We demonstrate that TRF2 interacts with Ku at telomeres and via residues in Ku70 helix 5 (α5), which are vital for NHEJ. We show that Ku's interaction with a TRF2 mutant that induces telomeric fusions is significantly impaired. Additionally, we demonstrate that Ku70 α5 is required for Ku self-association in live cells, which can bridge DNA ends. Together, these findings lead us to propose a model in which telomeres are directly protected from c-NHEJ via TRF2 impeding Ku's ability to synapse telomere ends.

Publication types

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

MeSH terms

  • Antigens, Nuclear / chemistry
  • Antigens, Nuclear / genetics
  • Antigens, Nuclear / metabolism*
  • DNA End-Joining Repair*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Ku Autoantigen
  • Models, Molecular
  • Protein Multimerization
  • Recombination, Genetic
  • Telomere / chemistry
  • Telomere / genetics
  • Telomere / metabolism*
  • Telomeric Repeat Binding Protein 2 / genetics
  • Telomeric Repeat Binding Protein 2 / metabolism*


  • Antigens, Nuclear
  • DNA-Binding Proteins
  • TERF2 protein, human
  • Telomeric Repeat Binding Protein 2
  • Xrcc6 protein, human
  • Ku Autoantigen