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Dissociation of the recombination control and the sequence-specific transactivation function of P53

Oncogene volume 18, pages 5773–5784 (1999)Cite this article

Abstract

Recently, we described a new biological function of p53 in inhibiting recombination processes when encountering mismatches in heteroduplexes (Dudenhöffer et al., 1998). Here, we characterized protein domains of p53 participating in this process by in vitro analysis of mutated p53 proteins, and by applying our SV40-based assay system on monkey cells, which express different p53 variants. We present evidence that both binding of artificial recombination intermediates and p53-dependent recombination control require an intact p53 core and the oligomerization domain, strongly suggesting that the recognition of DNA undergoing recombination represents an essential step of this genomic surveillance mechanism. Further analyses indicated a role of the C-terminus in negatively regulating recombination control, an effect which can be neutralized by concurrent mismatch recognition. p53 lacking the oligomerization domain totally lost its ability to suppress homologous recombination. The cancer-related mutant p53(273H) was also significantly defective in this function, although we observed only twofold reductions in the corresponding transactivation activities on p53-response elements in episomal constructs. HDM2, an inhibitor of p53's transcriptional and growth regulatory activities, interfered with the inhibition of DNA exchange processes by p53 only weakly. Thus, functions of p53 in recombination control can be structurally dissociated from p53-dependent transcriptional transactivation.

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Acknowledgements

We are grateful to Dr K Roemer, Universität Homburg/Saar, for the generous gift of the plasmid pCmdm2, to Dr S Braselmann, IMP Vienna, for constructs pMVGalERVP and pMV-7, to Dr H Abken, Institut für Genetik, Universität Bonn, for the plasmid phyg, and to Dr Katrin Will, Heinrich-Pette-Institut, Hamburg, for the vector pC53-4.2N3. We also wish to thank Thierry Soussi, University P et M Curie, Paris, for the generous gift of the baculoviruses designed for the expression of human p53 variants in insect cells. This work was supported by the Deutsche Forschungsgemeinschaft, grants DFG Wi 1376/1-2 and B1 of the Sonderforschungsbereich 545, and by the Deutsche Krebshilfe, grant 10-1281-Wi I. The Heinrich-Pette-Institut is supported by the Freie und Hansestadt Hamburg and by the Bundesministerium für Gesundheit.

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  1. Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, Martinistraße 52, Hamburg, D-20251, Germany

    Christine Dudenhöffer, Marion Kurth, Friedemann Janus, Wolfgang Deppert & Lisa Wiesmüller

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Dudenhöffer, C., Kurth, M., Janus, F. et al. Dissociation of the recombination control and the sequence-specific transactivation function of P53. Oncogene 18, 5773–5784 (1999). https://doi.org/10.1038/sj.onc.1202964

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