Negative Cell Cycle Regulation and DNA Damage-inducible Phosphorylation of the BRCT Protein 53BP1
Abstract
In a screen designed to discover suppressors of mitotic catastrophe, we identified the Xenopus ortholog of 53BP1 (X53BP1), a BRCT protein previously identified in humans through its ability to bind the p53 tumor suppressor. X53BP1 transcripts are highly expressed in ovaries, and the protein interacts with Xp53 throughout the cell cycle in embryonic extracts. However, no interaction between X53BP1 and Xp53 can be detected in somatic cells, suggesting that the association between the two proteins may be developmentally regulated. X53BP1 is modified via phosphorylation in a DNA damage-dependent manner that correlates with the dispersal of X53BP1 into multiple foci throughout the nucleus in somatic cells. Thus, X53BP1 can be classified as a novel participant in the DNA damage response pathway. We demonstrate that X53BP1 and its human ortholog can serve as good substrates in vitro as well as in vivo for the ATM kinase. Collectively, our results reveal that 53BP1 plays an important role in the checkpoint response to DNA damage, possibly in collaboration with ATM.
Additional Information
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc. Received for publication, August 22, 2000, and in revised form, October 6, 2000. Originally published In Press as doi:10.1074/jbc.M007665200 on October 20, 2000 We are grateful to the many people who contributed to and/or supported this project throughout its various stages. In particular, we thank Steve Elledge and David Cortez for numerous reagents and for support throughout the course of this study. We are grateful to Thanos Halazonetis for communicating results prior to publication. We thank Paul Mueller for use of the mitotic catastrophe screen and Dr. David Lane for the kind gift of Xenopus p53 antisera. We are indebted to Dr. Andrew Krieg for the gift of Xenopus EF-1alpha for Northern loading controls and to Dr. Ronald Kerman for permission to use the cesium irradiator. We also thank Tamara Tripic and Jason Grier for their efforts during the earlier stages of the project. We are also indebted to Rob Kirken and Mike Blackburn for experimental advice and assistance with the use of the fluorescence microscope, respectively. This work was supported in part by grants from the Ellison Medical Foundation and the Welch Foundation (to P.B.C.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF281071. [W.G.D. was an] Investigator of the Howard Hughes Medical Institute. [P.B.C. was a] Junior Research Scholar of the Ellison Medical Foundation.Files
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Additional details
- Eprint ID
- 5195
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- CaltechAUTHORS:XIAjbc01
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2006-10-04Created from EPrint's datestamp field
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2021-11-08Created from EPrint's last_modified field