Xq. Zhai et al., CISPLATIN-DNA ADDUCTS INHIBIT RIBOSOMAL-RNA SYNTHESIS BY HIJACKING THE TRANSCRIPTION FACTOR HUMAN UPSTREAM BINDING-FACTOR, Biochemistry (Easton), 37(46), 1998, pp. 16307-16315
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.