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

Jennifer Boyle, Takahiro Ueda, Kyu Seon Oh, Kyoko Imoto, Deborah Tamura, Jared Jagdeo, Sikandar G. Khan, Carine Nadem, John J. DiGiovanna, Kenneth H. Kraemer

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1194-1208
Number of pages15
JournalHuman Mutation
Volume29
Issue number10
DOIs
StatePublished - Oct 2008
Externally publishedYes

Fingerprint

Trichothiodystrophy Syndromes
Xeroderma Pigmentosum
DNA Damage
Mutation
DNA Repair
Neoplasms
Proteins
Skin Neoplasms
DNA
Transcription Factor TFIIH
Genes

Keywords

  • Confocal microscopy
  • DNA repair
  • ERCC2
  • Immunofluorescence
  • Skin cancer
  • TTD
  • Ultraviolet radiation
  • XP
  • XPD

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 (XPD) mutations : Cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy. / Boyle, Jennifer; Ueda, Takahiro; Oh, Kyu Seon; Imoto, Kyoko; Tamura, Deborah; Jagdeo, Jared; Khan, Sikandar G.; Nadem, Carine; DiGiovanna, John J.; Kraemer, Kenneth H.

In: Human Mutation, Vol. 29, No. 10, 10.2008, p. 1194-1208.

Research output: Contribution to journalArticle

Boyle, Jennifer ; Ueda, Takahiro ; Oh, Kyu Seon ; Imoto, Kyoko ; Tamura, Deborah ; Jagdeo, Jared ; Khan, Sikandar G. ; Nadem, Carine ; DiGiovanna, John J. ; Kraemer, Kenneth H. / Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 (XPD) mutations : Cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy. In: Human Mutation. 2008 ; Vol. 29, No. 10. pp. 1194-1208.
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abstract = "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.",
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AU - Boyle, Jennifer

AU - Ueda, Takahiro

AU - Oh, Kyu Seon

AU - Imoto, Kyoko

AU - Tamura, Deborah

AU - Jagdeo, Jared

AU - Khan, Sikandar G.

AU - Nadem, Carine

AU - DiGiovanna, John J.

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AB - 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.

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