Global and transcription-coupled repair of 8-oxoG is initiated by nucleotide excision repair proteins

Nat Commun. 2022 Feb 21;13(1):974. doi: 10.1038/s41467-022-28642-9.

Abstract

UV-DDB, consisting of subunits DDB1 and DDB2, recognizes UV-induced photoproducts during global genome nucleotide excision repair (GG-NER). We recently demonstrated a noncanonical role of UV-DDB in stimulating base excision repair (BER) which raised several questions about the timing of UV-DDB arrival at 8-oxoguanine (8-oxoG), and the dependency of UV-DDB on the recruitment of downstream BER and NER proteins. Using two different approaches to introduce 8-oxoG in cells, we show that DDB2 is recruited to 8-oxoG immediately after damage and colocalizes with 8-oxoG glycosylase (OGG1) at sites of repair. 8-oxoG removal and OGG1 recruitment is significantly reduced in the absence of DDB2. NER proteins, XPA and XPC, also accumulate at 8-oxoG. While XPC recruitment is dependent on DDB2, XPA recruitment is DDB2-independent and transcription-coupled. Finally, DDB2 accumulation at 8-oxoG induces local chromatin unfolding. We propose that DDB2-mediated chromatin decompaction facilitates the recruitment of downstream BER proteins to 8-oxoG lesions.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly
  • DNA Damage / radiation effects
  • DNA Glycosylases / metabolism
  • DNA Repair*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Knockdown Techniques
  • Gene Knockout Techniques
  • Guanine / analogs & derivatives*
  • Guanine / metabolism
  • Guanine / radiation effects
  • HEK293 Cells
  • Humans
  • Ultraviolet Rays / adverse effects
  • Xeroderma Pigmentosum Group A Protein / genetics
  • Xeroderma Pigmentosum Group A Protein / metabolism

Substances

  • Chromatin
  • DDB2 protein, human
  • DNA-Binding Proteins
  • XPA protein, human
  • Xeroderma Pigmentosum Group A Protein
  • XPC protein, human
  • 8-hydroxyguanine
  • Guanine
  • DNA Glycosylases
  • oxoguanine glycosylase 1, human