Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 (XPD) mutations: cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy.
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.
Boyle
Jennifer
J
DNA Repair Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4258, USA.
Ueda
Takahiro
T
Oh
Kyu-Seon
KS
Imoto
Kyoko
K
Tamura
Deborah
D
Jagdeo
Jared
J
Khan
Sikandar G
SG
Nadem
Carine
C
Digiovanna
John J
JJ
Kraemer
Kenneth H
KH
D000328:Adult; D002648:Child; D004249:DNA Damage / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D051758:Transcription Factor TFIIH / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D054463:Trichothiodystrophy Syndromes / Q000235:genetics* / Q000473:pathology; D014983:Xeroderma Pigmentosum / Q000150:complications / Q000235:genetics* / Q000473:pathology; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics / Q000378:metabolism; D051759:Xeroderma Pigmentosum Group D Protein / Q000032:analysis / Q000235:genetics*; D000099250:DNA Excision Repair Protein ERCC-5
D004265:DNA Helicases; D004268:DNA-Binding Proteins; D004720:Endonucleases; D009687:Nuclear Proteins; D051758:Transcription Factor TFIIH; D014157:Transcription Factors; D051760:Xeroderma Pigmentosum Group A Protein; D051759:Xeroderma Pigmentosum Group D Protein; D000099250:DNA Excision Repair Protein ERCC-5; C497314:XPA protein, human; C072022:XPBC-ERCC-3 protein; C497292:ERCC2 protein, human