| Project/Area Number |
16591114
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Dermatology
|
|---|
| Research Institution | Nara Medical University |
|---|
Principal Investigator |
KOBAYASHI Nobuhiko Nara Medical University, School of Medicine, Assistant Professor, 医学部, 講師 (70316074)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MORI Toshio Nara Medical University, School of Medicine, Associate Professor, 医学部, 助教授 (10115280)
|
|---|
| Project Period (FY) |
2004 – 2005
|
| Project Status |
Completed (Fiscal Year 2005)
|
| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
|
|---|
| Keywords | trichothiodystrophy / TFIIH / UV-induced skin cancer / xeroderma pigmentosum group D / ultraviolet-induced DNA damage / micropore UV irradiation / monoclonal antibody / visualization of DNA repair / DNA修復 / 発癌 / シクロブタン型ダイマー / (6-4)型ダイマー / ELISA / 免疫蛍光染色 |
|---|
| Research Abstract |
A photosensitive form of trichothiodystrophy (TTD) results from mutations in the same XPD gene as the DNA repair-deficient genetic disorder xeroderma pigmentosum group D (XP-D). Interestingly however, unlike XP-D, no increase in skin cancers appears in patients with TTD. In this study, we compared the ability to repair ultraviolet (UV)-induced DNA damage between TTD and XP-D cells to explain the cancer-free phenotype of TTD. The repair kinetics of cyclobutane pyrimidine dimers (CPD) and (6-4) photoproducts (6-4PP) was determined using an enzyme-linked immunosorbent assay. The accumulation of repair proteins (XPB and proliferating cell nuclear antigen) at localized DNA damage sites in the nucleus was detected using micropore UV irradiation combined with fluorescent antibody labeling. We found that both TTD and XP-D cells were deficient in the repair of CPD and of 6-4PP. UV sensitivity correlated well with the severity of repair defects. A TTD cell strain was more sensitive to UV than XP-D cell strains tested. In XP-D cells, mutations of the XPD gene impaired the helicase activity of the XPD protein resulting in the DNA repair defect. Mutations of the XPD gene in TTD cells, however, affected both the recruitment of the TFIIH complex to DNA damage sites and the TFIIH expression. Our results suggest that there is no major difference in the repair defect between TTD and XP-D, and that the cancer-free phenotype in TTD can be related to another role of TFIIH as a transcription factor. The impairment of the transcriptional activity might have an impact on the inhibition of malignant transformation in TTD cells having UV-induced gene mutations.
|
