Nucleic Acids Research, Vol 26, Issue 12 2831-2836, Copyright © 1998 by Oxford University Press
P Jordan and M Carmo-Fonseca
Cis -diammininedichloroplatinum(II) (cisplatin or cis -DDP) is a DNA-
damaging agent that is widely used in cancer chemotherapy. Cisplatin
crosslinks DNA and the resulting adducts interact with proteins that
contain high-mobility-group (HMG) domains, such as UBF(upstream binding
factor). UBF is a transcription factor that binds to the promoter of
ribosomal RNA (rRNA) genes thereby supporting initiation of transcription
by RNA polymerase I. Here we report that cisplatin causes a redistribution
of UBF in the nucleolus of human cells, similar to that observed after
inhibition of rRNA synthesis. A similar redistribution was observed for the
major components of the rRNA transcription machinery, namely TBP, TAFIs and
RNA polymerase I. Furthermore, we provide for the first time direct in vivo
evidence that cisplatin blocks synthesis of rRNA, while activity of RNA
polymerase II continues to be detected throughout the nucleus. The
clinically ineffective trans isomer (trans -DDP) does not alter the
localization of either UBF or other components of the RNA polymerase I
transcription machinery. These results suggest that disruption of rRNA
synthesis, which is stimulated in proliferating cells, plays an important
role in the clinical success of cisplatin.
ARTICLES
Cisplatin inhibits synthesis of ribosomal RNA in vivo
Institute of Histology and Embryology, Faculty of Medicine, University of Lisbon, 1699 Lisboa Codex, Portugal.
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