CISPLATIN-DNA ADDUCTS INHIBIT RIBOSOMAL-RNA SYNTHESIS BY HIJACKING THE TRANSCRIPTION FACTOR HUMAN UPSTREAM BINDING-FACTOR

Several eukaryotic cellular proteins recognize DNA modified by the ant icancer drug cisplatin (cis-diamminedichloroplatinum(II) or cis-DDP); among these proteins is a class of DNA-binding molecules containing th e HMG (high-mobility group) box DNA recognition motif. We have previou sly reported the extraordinarily high binding activity to cisplatin ad ducts by human upstream binding factor (hUBF), an HMG box containing t ranscription factor that stimulates ribosomal RNA synthesis (Treiber e t al. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 5672-5676). In the pres ent study, we discovered that (1) hUBF interacted selectively with DNA lesions formed by therapeutically effective platinum compounds [Pt(en )Cl-2] and [Pt(dach)Cl-2], in addition to the lesions formed by cis-DD P, suggesting a possible association with their anticancer effect; (2) multiple HMG boxes contributed additively to the hUBF-adduct interact ion, providing a possible explanation for the unusually high affinity of hUBF for cis-DDP adducts as compared to the lower affinities of oth er HMG box proteins; and (3) ribosomal RNA transcription in a reconsti tuted system is specifically inhibited in the presence of cis-DDP addu cts. In this third experiment, a ratio of adducts/promoter of similar to 4:1 completely abolished the transcription activated by hUBF. Taken together, these data lend support to the view that transcription fact ors involved in cellular growth regulation, such as ribosomal RNA tran scription, may be hijacked by cis-DDP adducts resulting in functional inhibition.