Miz1 and HectH9 regulate the stability of the checkpoint protein, TopBP1

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...

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Published in:	The EMBO journal 2008-11, Vol.27 (21), p.2851-2861
Main Authors:	Herold, Steffi, Hock, Andreas, Herkert, Barbara, Berns, Katrien, Mullenders, Jasper, Beijersbergen, Roderick, Bernards, Rene, Eilers, Martin
Format:	Article
Language:	eng
Subjects:	Amino Acid Substitution Ataxia Telangiectasia Mutated Proteins Atr Binding sites Carrier Proteins - metabolism Cell Cycle Cell Cycle Proteins - metabolism Cell Line, Tumor Cellular biology Chromatin Chromatin - metabolism Cyclin-Dependent Kinase Inhibitor p21 - metabolism DNA-Binding Proteins - metabolism Humans Miz1 Models, Biological Molecular biology Myc Nuclear Proteins - metabolism Protein Inhibitors of Activated STAT - metabolism Protein-Serine-Threonine Kinases - metabolism Proteins Proto-Oncogene Proteins c-myc - metabolism Signal Transduction TopBP1 Ubiquitin-Protein Ligases - metabolism
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Summary:	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.
ISSN:	0261-4189 1460-2075