Abstract
Heteroduplex joints represent intermediates of Rad51-dependent recombination processes, which are recognized by p53 with extremely high affinities, in a manner independent of the DNA sequence content. To determine the structural elements required for complex formation, we monitored DNA-binding by protection against restriction endonuclease cleavage. We show that wild-type (wt) p53 interacts with heteroduplex joints in the proximity of the flexible junction. Association of p53 within this junction region was also observed with preformed Rad51-heteroduplex complexes, whereas SSB counteracted p53 binding. At a distance of 31 bp from the junction p53 established very few contacts with the heteroduplex, despite the presence of an A–G mismatch. Consistently, p53-dependent exonucleolytic degradation decreased when we raised the distance between the junction and the heteroduplex terminus by 27 bp. Different from the cancer-related mutant p53(273H), which did not recognize the junction, tetramerization defective p53-1262 was protection competent but displayed reduced complex stability in gel shifts. Moreover, p53-1262 performed exonucleolytic activities towards ssDNA like wtp53, but reduced degradation of heteroduplex joints. These results suggest that during recombination wild-type p53, as a tetramer, stably binds to strand transfer regions, enabling the protein to exonucleolytically correct heteroduplex intermediates early after strand invasion.
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Acknowledgements
Our special thanks go to Prof Dr John Jenkins, Marie Curie Research Institute, Oxted, Surrey, UK, for the generous gift of the baculoviral expression plasmid for p53-1262. We are grateful to Anke Osterloh and Marco Littek for competent experimental assistance. This work was supported by the Deutsche Forschungsgemeinschaft, grants Wi 1376/1-4 and -5 and grant 10-1281-Wi I by the Deutsche Krebshilfe, the Dr Mildred Scheel Stiftung. S. Süsse was supported by the FAZIT-Stiftung, Frankfurt a.M.
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Janz, C., Süsse, S. & Wiesmüller, L. p53 and recombination intermediates: role of tetramerization at DNA junctions in complex formation and exonucleolytic degradation. Oncogene 21, 2130–2140 (2002). https://doi.org/10.1038/sj.onc.1205292
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DOI: https://doi.org/10.1038/sj.onc.1205292
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