Highly purified p53 protein from different sources was able to degrade DNA with a 3'-to-5' polarity, yielding deoxynucleoside monophosphates as reaction products. This exonuclease activity was dependent on Mg2+ and inhibited by addition of 5 mM nucleoside monophosphates. This exonuclease activity is intrinsic to the wild-type p53 protein: it copurified with p53 during p53 preparation; only purified wild-type p53, but not identically purified mutant p53 proteins displayed exonuclease activity; the exonuclease activity could be reconstituted from SDS gel-purified and urea-renatured p53 protein and mapped to the core domain of the p53 molecule; and finally, purified p53 protein could be UV-cross-linked to GMP. A p53-intrinsic exonuclease activity should substantially extend our view on the role of p53 as a "guardian of the genome."

When growth‐arrested mouse fibroblasts re‐entered the cell‐cycle, the rise in tumour suppressor p53 mRNA level markedly preceded the rise in expression of the p53 protein. Furthermore, gamma‐irradiation of such cells led to a rapid increase in p53 protein biosynthesis even in the presence of the transcription inhibitor actinomycin D. Both findings strongly suggest that p53 biosynthesis in these cells is regulated at the translational level. We present evidence for an autoregulatory control of p53 expression by a negative feed‐back loop: p53 mRNA has a predicted tendency to form a stable stem‐loop structure that involves the 5′‐untranslated region (5′‐UTR) plus some 280 nucleotides of the coding sequence. p53 binds tightly to the 5′‐UTR region and inhibits the translation of its own mRNA, most likely mediated by the p53‐intrinsic RNA re‐annealing activity. The inhibition of p53 biosynthesis requires wild‐type p53, as it is not observed with MethA mutant p53, p53‐catalysed translational inhibition is selective; it might be restricted to p53 mRNA and a few other mRNAs that are able to form extensive stem‐loop structures. Release from negative feed‐back regulation of p53 biosynthesis, e.g. after damage‐induced nuclear transport of p53, might provide a means for rapidly increasing p53 protein levels when p53 is required to act as a cell‐cycle checkpoint determinant after DNA damage.