Inhibition of transcription factor binding by ultraviolet-induced pyrimidine dimers.
The formation of DNA photoproducts by ultraviolet (UV) light is responsible for the induction of mutations and the development of skin cancer. Cis-syn cyclobutane pyrimidine dimers (pyrimidine dimers) are the most frequent lesions produced in DNA by UV irradiation. Besides being mutagenic, pyrimidine dimers may interfere with other important DNA-dependent processes. To analyze the effects of pyrimidine dimers on the ability of DNA sequences to be recognized by trans-acting factors, we have incorporated site-specific T-T dimers into oligonucleotides containing the recognition sequences of the sequence-specific transcription factors E2F, NF-Y, AP-1, NF kappa B, and p53. In each case, presence of the photodimer strongly inhibited binding of the respective transcription factor complex. Reduction of binding varied between 11- and 60-fold. The results indicate that the most common UV-induced DNA lesion can interfere severely with binding of several important cell cycle regulatory and DNA damage responsive transcription factors. We suggest that inhibition of transcription factor binding may be a major biological effect of UV radiation since promoter regions are known to be repaired inefficiently and since UV damage can deregulate the function of a large number of different factors.
Tommasi
S
S
Department of Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
Swiderski
P M
PM
Tu
Y
Y
Kaplan
B E
BE
Pfeifer
G P
GP
D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D003503:Cyclobutanes / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D043224:Deoxyribonuclease (Pyrimidine Dimer); D004591:Electrophoresis, Polyacrylamide Gel; D004706:Endodeoxyribonucleases; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011740:Pyrimidine Dimers / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014466:Ultraviolet Rays
D003503:Cyclobutanes; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D011740:Pyrimidine Dimers; D014157:Transcription Factors; D004706:Endodeoxyribonucleases; D043224:Deoxyribonuclease (Pyrimidine Dimer)