Article
- The EMBO Journal (2008) 27, 2851 - 2861
- doi:10.1038/emboj.2008.200
Published online: 16 October 2008
Subject Category:
Miz1 and HectH9 regulate the stability of the checkpoint protein, TopBP1
Steffi Herold1,a, Andreas Hock1,a, Barbara Herkert1, Katrien Berns2, Jasper Mullenders2, Roderick Beijersbergen2, Rene Bernards2 and Martin Eilers1
- Institute of Molecular Biology and Tumor Research, Philipps University Marburg, Marburg, Germany
- Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands
Correspondence to:
Martin Eilers, Institute of Molecular Biology and Tumor Research, Philipps University Marburg, Emil-Mannkopff-Strasse 2, 35033 Marburg, Germany. Tel.: +49 6421 286 6410; Fax: +49 6421 286 5196; E-mail: eilers@imt.uni-marburg.de
aThese authors contributed equally to this work
Received 24 April 2008; Accepted 8 September 2008
Abstract
The Myc-associated zinc-finger protein, Miz1, activates transcription of the p21cip1 gene in response to UV irradiation. Miz1 associates with topoisomerase II binding protein1 (TopBP1), an essential activator of the Atr kinase. We show here that Miz1 is required for the recruitment of a fraction of TopBP1 to chromatin, for the protection of TopBP1 from proteasomal degradation and for Atr-dependent signal transduction. TopBP1 that is not bound to chromatin is degraded by the HectH9 (Mule, ARF-BP1 and HUWE1) ubiquitin ligase. Myc antagonizes the binding of TopBP1 to Miz1; as a result, expression of Myc leads to dissociation of TopBP1 from chromatin, reduces the amount of total TopBP1 and attenuates Atr-dependent signal transduction. Our data show that Miz1 and Myc affect the activity of the Atr checkpoint through their effect on TopBP1 chromatin association and stability.
Keywords:
- Atr,
- Miz1,
- Myc,
- TopBP1
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