The viral oncoprotein tax sequesters DNA damage response factors by tethering MDC1 to chromatin

J Biol Chem. 2010 Oct 22;285(43):32897-32905. doi: 10.1074/jbc.M110.146373. Epub 2010 Aug 20.


Infection with human T-cell leukemia virus induces cellular genomic instability mediated through the viral oncoprotein Tax. Here we present evidence that Tax undermines the cellular DNA damage response by sequestration of damage response factors. We show by confocal microscopy that Tax forms damage-independent nuclear foci that contain DNA-PK, BRCA1, and MDC1. Tax sequesters MDC1 to chromatin sites distinct from classic ionizing radiation-induced foci. The recruitment of MDC1 is competitive between the two foci. The N-terminal region of Tax is sufficient for foci localization, and the C-terminal half is critical for binding to MDC1 and recruitment of additional response factors. Tax expression and DNA damage response factor recruitment repressed the formation of ionizing radiation-induced Nbs1-containing foci. The Tax-induced "pseudo" DNA damage response results in phosphorylation and monoubiquitylation of H2AX, which is ablated by siRNA suppression of MDC1. These data support a model for virus-induced genomic instability in which viral oncogene-induced damage-independent foci compete with normal cellular DNA damage response.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • Cell Cycle Proteins
  • Cell Line
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Cell Nucleus / pathology
  • Cell Nucleus / virology
  • Chromatin / genetics
  • Chromatin / metabolism*
  • DNA Damage*
  • DNA-Activated Protein Kinase / genetics
  • DNA-Activated Protein Kinase / metabolism
  • Gene Products, tax / genetics
  • Gene Products, tax / metabolism*
  • Genomic Instability*
  • Human T-lymphotropic virus 1 / genetics
  • Human T-lymphotropic virus 1 / metabolism*
  • Humans
  • Models, Biological*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation / genetics
  • Phosphorylation / radiation effects
  • Radiation, Ionizing
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Ubiquitination / genetics
  • Ubiquitination / radiation effects


  • Adaptor Proteins, Signal Transducing
  • BRCA1 Protein
  • BRCA1 protein, human
  • Cell Cycle Proteins
  • Chromatin
  • Gene Products, tax
  • MDC1 protein, human
  • Nuclear Proteins
  • Trans-Activators
  • tax protein, Human T-lymphotrophic virus 1
  • DNA-Activated Protein Kinase
  • PRKDC protein, human