Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 (XPD) mutations: cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy

Hum Mutat. 2008 Oct;29(10):1194-208. doi: 10.1002/humu.20768.


Patients with xeroderma pigmentosum (XP) have a 1,000-fold increase in ultraviolet (UV)-induced skin cancers while trichothiodystrophy (TTD) patients, despite mutations in the same genes, ERCC2 (XPD) or ERCC3 (XPB), are cancer-free. Unlike XP cells, TTD cells have a nearly normal rate of removal of UV-induced 6-4 photoproducts (6-4PP) in their DNA and low levels of the basal transcription factor, TFIIH. We examined seven XP, TTD, and XP/TTD complex patients and identified mutations in the XPD gene. We discovered large differences in nucleotide excision repair (NER) protein recruitment to sites of localized UV damage in TTD cells compared to XP or normal cells. XPC protein was rapidly localized in all cells. XPC was redistributed in TTD, and normal cells by 3 hr postirradiation, but remained localized in XP cells at 24-hr postirradiation. In XP cells recruitment of other NER proteins (XPB, XPD, XPG, XPA, and XPF) was also delayed and persisted at 24 hr (p<0.001). In TTD cells with defects in the XPD, XPB, or GTF2H5 (TTDA) genes, in contrast, recruitment of these NER proteins was reduced compared to normals at early time points (p<0.001) and remained low at 24 hr postirradiation. These data indicate that in XP persistence of NER proteins at sites of unrepaired DNA damage is associated with greatly increased skin cancer risk possibly by blockage of translesion DNA synthesis. In contrast, in TTD, low levels of unstable TFIIH proteins do not accumulate at sites of unrepaired photoproducts and may permit normal translesion DNA synthesis without increased skin cancer.

MeSH terms

  • Adult
  • Child
  • DNA Damage / genetics*
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA Repair / genetics*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endonucleases / genetics
  • Endonucleases / metabolism
  • Humans
  • Male
  • Mutation*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Skin Neoplasms / etiology
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Transcription Factor TFIIH / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Trichothiodystrophy Syndromes / genetics*
  • Trichothiodystrophy Syndromes / pathology
  • Xeroderma Pigmentosum / complications
  • Xeroderma Pigmentosum / genetics*
  • Xeroderma Pigmentosum / pathology
  • Xeroderma Pigmentosum Group A Protein / genetics
  • Xeroderma Pigmentosum Group A Protein / metabolism
  • Xeroderma Pigmentosum Group D Protein / analysis
  • Xeroderma Pigmentosum Group D Protein / genetics*


  • DNA excision repair protein ERCC-5
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Transcription Factors
  • XPA protein, human
  • Xeroderma Pigmentosum Group A Protein
  • XPBC-ERCC-3 protein
  • Transcription Factor TFIIH
  • Endonucleases
  • DNA Helicases
  • Xeroderma Pigmentosum Group D Protein
  • ERCC2 protein, human