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Wild-type p53 stimulates homologous recombination upon sequence-specific binding to the ribosomal gene cluster repeat

Oncogene volume 24, pages 4183–4192 (2005)Cite this article

Abstract

p53 plays a central role in the maintenance of the genome integrity, both as a gatekeeper and a caretaker. Sequence-specific recognition of DNA is underlying the ability of p53 to transcriptionally transactivate target genes during checkpoint control and to regulate DNA replication at the TGCCT repeat from the ribosomal gene cluster (RGC). In contrast, suppression of recombination by p53 has been observed with nonconsensus DNA sequences. In this study, we discovered that wild-type p53 stimulates homologous recombination adjacent to the RGC repeat, whereas downregulation is seen with a mutated version thereof and with a microsatellite repeat sequence. Analysis of the causes possibly underlying the enhancement of homologous recombination revealed that p53 binding to the RGC element delays DNA synthesis. This was demonstrated after integration of the corresponding DNA fragments into our Simian virus 40-based model system, which was used to study recombination on replicating minichromosomes. Differently, with plasmid-based substrates, p53 did not stimulate recombination at the RGC sequence. Thus, in combination with our previous findings, p53 may promote homologous recombination by two separate mechanisms involving either molecular interactions with topoisomerase I or/and by specific binding to certain genomic regions, thereby causing replication fork stalling and recombination.

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Acknowledgements

We are grateful to Richard P Bowater, University of East Anglia Norwich, and Robert D Wells, Texas Medical Center, for construct pRW3246, to Professor Dr B Vogelstein, John Hopkins Oncology Center, Baltimore, for pSK-45-13-2-PyCAT and pSK-89-15-1-PyCAT. We thank Evelyn Bendrat for experimental assistance with DNA cloning. This work was supported by the Dr Mildred Scheel Stiftung (Deutsche Krebshilfe) Grant 10-1907-Wi 2, by the Deutsche Forschungsgemeinschaft Grant Wi 1376/3-1, and by the Land Baden-Württemberg, Forschungsschwerpunktprogramm: Fehlregulation von Apoptose als Grundlage für Krankheit.

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Authors and Affiliations

  1. Universitätsfrauenklinik, Prittwitzstrasse 43, D-89075, Ulm, Germany

    Gisa S Boehden, Cindy Baumann, Simone Siehler & Lisa Wiesmüller

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

    Gisa S Boehden & Lisa Wiesmüller

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  1. Gisa S Boehden
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Correspondence to Lisa Wiesmüller.

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Boehden, G., Baumann, C., Siehler, S. et al. Wild-type p53 stimulates homologous recombination upon sequence-specific binding to the ribosomal gene cluster repeat. Oncogene 24, 4183–4192 (2005). https://doi.org/10.1038/sj.onc.1208592

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