CISPLATIN-DAMAGED AND UV-DAMAGED DNA LURE THE BASAL TRANSCRIPTION FACTOR TFIID TBP/

A connection between transcription and DNA repair was demonstrated pre viously through the characterization of TFIIH. Using filter binding as well as in vitro transcription challenge competition assays, me now s how that the promoter recognition factor TATA box-binding protein (TBP )/TFIID binds selectively to and is sequestered by cisplatin-or UV-dam aged DNA, either alone or in the context of a larger protein complex i ncluding TFIIH, Computer-assisted 3D structural analysis reveals a rem arkable similarity between the structure of the TATA box as found in i ts TBP complex and that of either platinated or UV-damaged oligonucleo tides, Thus, cisplatin-treated or UV-irradiated DNA could be used as a competing binding site which may lure TBP/TFIID away from its normal promoter sequence, partially explaining the phenomenon of DNA damage-i nduced inhibition of RNA synthesis, Consistent with an involvement of damaged DNA-specific binding of TBP in inhibiting transcription, we fi nd that microinjection of additional TBP in living human fibroblasts a lleviates the reduction in RNA synthesis after UV irradiation, Future anticancer drugs could be designed with the consideration of lesion re cognition by TBP and their ability to reduce transcription.