Inhibition of RNA polymerase II as a trigger for the p53 response

The mechanisms by which the p53 response is triggered following exposure to DNA-damaging agents have not yet been clearly elucidated. We and others ha ve previously suggested that blockage of RNA polymerase II may be the trigg er for induction of the p53 response following exposure to ultraviolet ligh t. Here we report on the correlation between inhibition of mRNA synthesis a nd the induction of p53, p21(WAF1) and apoptosis in diploid human fibroblas ts treated with either UV light, cisplatin or the RNA synthesis inhibitors actinomycin D, DRB, H7 and alpha-amanitin. Exposure to ionizing radiation o r the proteasome inhibitor LLnL, however, induced p53 and p21(WAF1) without affecting mRNA synthesis. Importantly, induction of p53 by the RNA synthes is or proteasome inhibitors did not correlate with the induction of DNA str and breaks. Furthermore, cisplatin-induced accumulation of active p53 in re pair-deficient XP-A cells occurred despite the lack of DNA strand break ind uction. Our results suggest that the induction of the p53 response by certa in toxic agents is not triggered by DNA strand breaks but rather, may be li nked to inhibition of mRNA synthesis either directly by the poisoning of RN A polymerase II or indirectly by the induction of elongation-blocking DNA l esions.