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Molecular and Cellular Biology, December 2003, p. 8960-8969, Vol. 23, No. 24
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.24.8960-8969.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Involvement of the DNA Repair Protein hHR23 in p53 Degradation

Sandra Glockzin,1 Francois-Xavier Ogi,2 Arnd Hengstermann,1 Martin Scheffner,1 and Christine Blattner2*

Zentrum für Biochemie, Medizinische Fakultät, Universität zu Köln, 50931 Cologne,1 Institut für Toxikologie und Genetik, Forschungszentrum Karlsruhe, 76021 Karlsruhe, Germany2

Received 12 May 2003/ Returned for modification 11 July 2003/ Accepted 11 September 2003

The stability of the tumor suppressor protein p53 is regulated via the ubiquitin-proteasome-dependent proteolytic pathway. Like most substrates of this pathway, p53 is modified by the attachment of polyubiquitin chains prior to proteasome-mediated degradation. However, the mechanism(s) involved in the delivery of polyubiquitylated p53 molecules to the proteasome are currently unclear. Here, we show that the human DNA repair protein hHR23 binds to polyubiquitylated p53 via its carboxyl-terminal ubiquitin-associated (Uba) domain shielding p53 from deubiquitylation in vitro and in vivo. In addition, downregulation of hHR23 expression within cells by RNA interference results in accumulation of p53. Since the Ubl domain of hHR23 has been shown to interact with the 26S proteasome, we propose that hHR23 is intrinsically involved in the delivery of polyubiquitylated p53 molecules to the proteasome. In this model, the Uba domain of hHR23 binds to polyubiquitin chains formed on p53 and protects them from deubiquitylation, while the Ubl domain delivers the polyubiquitylated p53 molecules to the proteasome.

* Corresponding author. Mailing address: Institut für Genetik, Forschungszentrum Karlsruhe, 76021 Karlsruhe, Germany. Phone: 49-247-822634. Fax: 49-7247-823354. E-mail: christine.blattner{at}itg.fzk.de.

Molecular and Cellular Biology, December 2003, p. 8960-8969, Vol. 23, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.24.8960-8969.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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