Granzyme A, which causes single-stranded DNA damage, targets the double-strand break repair protein Ku70

EMBO Rep. 2006 Apr;7(4):431-7. doi: 10.1038/sj.embor.7400622. Epub 2006 Jan 20.


Granzyme A (GzmA) induces caspase-independent cell death with morphological features of apoptosis. Here, we show that GzmA at nanomolar concentrations cleaves Ku70, a key double-strand break repair (DSBR) protein, in target cells. Ku70 is cut after Arg(301), disrupting Ku complex binding to DNA. Cleaving Ku70 facilitates GzmA-mediated cell death, as silencing Ku70 by RNA interference increases DNA damage and cell death by GzmB cluster-deficient cytotoxic T lymphocytes or by GzmA and perforin, whereas Ku70 overexpression has the opposite effect. Ku70 has two known antiapoptotic effects-facilitating DSBR and sequestering bax to prevent its translocation to mitochondria. However, GzmA triggers single-stranded, not double-stranded, DNA damage, and GzmA-induced cell death does not involve bax. Therefore, Ku70 has other antiapoptotic functions in GzmA-induced cell death, which are blocked when GzmA proteolyses Ku70.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Nuclear / genetics
  • Antigens, Nuclear / metabolism*
  • Arginine / genetics
  • Arginine / metabolism
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • DNA / genetics
  • DNA / metabolism*
  • DNA Damage* / drug effects
  • DNA Repair*
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation
  • Granzymes
  • Humans
  • Ku Autoantigen
  • Membrane Glycoproteins / pharmacology
  • Mice
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • Protease Inhibitors / pharmacology
  • Protein Binding
  • Serine Endopeptidases / metabolism*
  • Serine Endopeptidases / pharmacology
  • T-Lymphocytes, Cytotoxic / metabolism


  • Antigens, Nuclear
  • DNA-Binding Proteins
  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Protease Inhibitors
  • Perforin
  • DNA
  • Arginine
  • Granzymes
  • Serine Endopeptidases
  • GZMA protein, human
  • Xrcc6 protein, human
  • Xrcc6 protein, mouse
  • Ku Autoantigen