DNA damage detection in nucleosomes involves DNA register shifting

Nature. 2019 Jul;571(7763):79-84. doi: 10.1038/s41586-019-1259-3. Epub 2019 May 29.


Access to DNA packaged in nucleosomes is critical for gene regulation, DNA replication and DNA repair. In humans, the UV-damaged DNA-binding protein (UV-DDB) complex detects UV-light-induced pyrimidine dimers throughout the genome; however, it remains unknown how these lesions are recognized in chromatin, in which nucleosomes restrict access to DNA. Here we report cryo-electron microscopy structures of UV-DDB bound to nucleosomes bearing a 6-4 pyrimidine-pyrimidone dimer or a DNA-damage mimic in various positions. We find that UV-DDB binds UV-damaged nucleosomes at lesions located in the solvent-facing minor groove without affecting the overall nucleosome architecture. In the case of buried lesions that face the histone core, UV-DDB changes the predominant translational register of the nucleosome and selectively binds the lesion in an accessible, exposed position. Our findings explain how UV-DDB detects occluded lesions in strongly positioned nucleosomes, and identify slide-assisted site exposure as a mechanism by which high-affinity DNA-binding proteins can access otherwise occluded sites in nucleosomal DNA.

MeSH terms

  • Cryoelectron Microscopy
  • DNA / chemistry
  • DNA / metabolism*
  • DNA / radiation effects
  • DNA / ultrastructure*
  • DNA Damage*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / ultrastructure
  • Histones / chemistry
  • Histones / metabolism
  • Histones / ultrastructure
  • Humans
  • Models, Molecular
  • Nucleosomes / genetics
  • Nucleosomes / metabolism*
  • Nucleosomes / radiation effects
  • Nucleosomes / ultrastructure*
  • Pyrimidine Dimers / analysis*
  • Pyrimidine Dimers / chemistry
  • Pyrimidine Dimers / genetics
  • Thermodynamics
  • Ultraviolet Rays / adverse effects


  • DDB1 protein, human
  • DDB2 protein, human
  • DNA-Binding Proteins
  • Histones
  • Nucleosomes
  • Pyrimidine Dimers
  • pyrimidine-pyrimidone dimer
  • DNA