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Miz1 and HectH9 regulate the stability of the checkpoint protein, TopBP1
Author(s) -
Herold Steffi,
Hock Andreas,
Herkert Barbara,
Berns Katrien,
Mullenders Jasper,
Beijersbergen Roderick,
Bernards Rene,
Eilers Martin
Publication year - 2008
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2008.200
Subject(s) - biology , g2 m dna damage checkpoint , chek1 , cell cycle protein , protein stability , microbiology and biotechnology , dna binding protein , cell cycle checkpoint , cancer research , computational biology , genetics , cell cycle , transcription factor , cancer , gene
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.