INHIBITION OF TRANSCRIPTION FACTOR-BINDING BY ULTRAVIOLET-INDUCED PYRIMIDINE DIMERS

The formation of DNA photoproducts by ultraviolet (UV) light is respon sible for the induction of mutations and the development of skin cance r. Cis-syn cyclobutane pyrimidine dimers (pyrimidine dimers) are the m ost frequent lesions produced in DNA by UV irradiation. Besides being mutagenic, pyrimidine dimers may interfere with other important DNA-de pendent 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 boolean AND T dimers into oligonucle otides containing the recognition sequences of the sequence-specific t ranscription factors E2F, NF-Y, AP-1, NF kappa B, and p53. In each cas e, presence of the photodimer strongly inhibited binding of the respec tive 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 c ell cycle regulatory and DNA damage responsive transcription factors. We suggest that inhibition of transcription factor binding may be a ma jor biological effect of UV radiation since promoter regions are known to be repaired inefficiently and since UV damage can deregulate the f unction of a large number of different factors.