Distinct faces of the Ku heterodimer mediate DNA repair and telomeric functions

Nat Struct Mol Biol. 2007 Apr;14(4):301-7. doi: 10.1038/nsmb1214. Epub 2007 Mar 11.


The Ku heterodimer, comprised of Ku70 and Ku80 subunits, is a conserved complex involved in nonhomologous end-joining (NHEJ). However, it also functions in maintenance of telomeres, chromosome termini normally resistant to end-joining events. To elucidate the spatial organization of these functions, we rationally guided Ku mutagenesis in yeast with real-valued evolutionary trace (rvET). This revealed two ancestrally related alpha-helices: one on the Ku70 surface that is required in yeast for NHEJ, and a second on the Ku80 surface that is required in yeast for telomeric heterochromatin formation. When bound to a DNA end, the surface containing the NHEJ-specific Ku70 helix is oriented toward the DNA terminus, whereas the surface containing the telomeric function-specific Ku80 helix faces inward, toward telomeric chromatin, when bound to a telomere. We propose a 'two-face' model for Ku and that divergent evolution of these faces allowed Ku's dual role in NHEJ and telomere maintenance.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Antigens, Nuclear / chemistry*
  • Antigens, Nuclear / metabolism*
  • Cluster Analysis
  • DNA Repair*
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism*
  • Dimerization
  • Humans
  • Ku Autoantigen
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation / genetics
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Recombination, Genetic / genetics
  • Saccharomyces cerevisiae / cytology
  • Saccharomyces cerevisiae / metabolism*
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae / metabolism
  • Structure-Activity Relationship
  • Telomere / metabolism*


  • Antigens, Nuclear
  • DNA-Binding Proteins
  • SIR4 protein, S cerevisiae
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae
  • Xrcc6 protein, human
  • Ku Autoantigen