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Carcinogenesis, Vol. 20, No. 8, 1439-1444, August 1999
© 1999 Oxford University Press

Cancer Biology

PolyADP-ribose-mediated regulation of p53 complexed with topoisomerase I following ionizing radiation

Heather M. Smith and Andrew J. Grosovsky1

Environmental Toxicology Program, University of California, 5419 Boyce Hall, Riverside, CA 92521, USA

This investigation demonstrates that the p53 and topoisomerase I (topo I) proteins which form a molecular complex in vivo are polyADP ribosylated following 1 Gy of {gamma} irradiation. Immunoprecipitations using a topo I monoclonal antibody were performed on protein extracts from {gamma}-irradiated TK6 human lymphoblastoid cells. Western blots on topo I immunoprecipitations probed with a polyADP-ribose polymer antibody demonstrated that several proteins, including p53, are co-immunoprecipitated with topo I. Furthermore, p53 and topo I are ADP ribosylated within 15 min following {gamma} irradiation. Unlike the other proteins within the complex, p53 is polyADP ribosylated at low levels in non-irradiated cells, and it is also the most heavily polyADP ribosylated following irradiation. Radiation induced polyADP ribosylation persists for at least 48 h following exposure. The DNA damage response does not involve the recruitment of free p53 to complex with topo I; the amount of p53 protein complexed with topo I was found to be independent of radiation exposure. It has recently been reported that p53 acts to catalytically stimulate the activity of topo I in the absence of DNA damage. We hypothesize that the rapid modification of the complex by polyADP ribosylation following radiation is a regulatory response to diminish topo I cleavage in the presence of DNA damage.

Abbreviations: PARP, polyADP-ribose polymerase; topo I, topoisomerase I

1 To whom correspondence should be addressed Email: grosovsky{at}ucr.edu


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