Cancer Research 60:4538-4543 (2000)

P53 Dependence of Topoisomerase I Recruitment in vivo

Abstract

DNA damage is attended by rapid recruitment of endogenous type I topoisomerase (topo I) into covalent cleavage complexes with genomic DNA in vivo.   In contrast, endogenous topoisomerase II alpha and beta are not stimulated by DNA damage. We show that topo I and p53 physically interact at arrested topo I-genomic DNA covalent complexes in vivo, suggesting that p53 directly stimulates topo I activity and damage to the genome of the afflicted cell.  Moreover, cells that express wild type p53 are most proficient at recruiting topo I following DNA damage; however, the p53 dependence is conditional since topo I recruitment following DNA damage can be restored if p53 mutant cells (containing a single mutant allele) are artificially held in G₁.  In contrast, p53 null mutants do not recruit topo I after DNA damage under any conditions (although camptothecin dependent topo I/DNA complexes readily form in the nulls).   These results show that topo I activation following DNA damage is p53 dependent.  It also depends upon the cell cycle in a way that is very different from that observed with DNA replication dependent, camptothecin mediated DNA breaks. The data suggest a model where p53 activates topo I which inflicts additional genomic damage after the initial UV damage events. Topoisomerases therefore contribute to the p53 commitment to apoptosis and topo I might assist in elimination of DNA damaged cells as part of the cellular proofreading function inherent in the p53 pathway.

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