Communicated by Richard Wooster
Article first published online: 9 MAY 2008
This article is a US Government work, and, as such, is in the public domain in the United States of America. Published in 2008 by Wiley-Liss, Inc.
Volume 29, Issue 10, pages 1194–1208, October 2008
How to Cite
Boyle, J., Ueda, T., Oh, K.-S., Imoto, K., Tamura, D., Jagdeo, J., Khan, S. G., Nadem, C., DiGiovanna, J. J. and Kraemer, K. H. (2008), 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., 29: 1194–1208. doi: 10.1002/humu.20768
This article is a US Government work, and, as such, is in the public domain in the United States of America.
- Issue published online: 23 SEP 2008
- Article first published online: 9 MAY 2008
- Manuscript Accepted: 28 JAN 2008
- Manuscript Received: 14 NOV 2007
- Intramural Research Program of the National Institutes of Health
- Center for Cancer Research, National Cancer Institute
- DNA repair;
- skin cancer;
- ultraviolet radiation;
- confocal microscopy;
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. Hum Mutat 0, 1–15, 2008. Published 2008 Wiley-Liss, Inc.