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The Mre11-Rad50-Nbs1 complex mediates activation of TopBP1 by ATM

Yoo, Hae Yong and Kumagai, Akiko and Shevchenko, Anna and Shevchenko, Andrej and Dunphy, William G. (2009) The Mre11-Rad50-Nbs1 complex mediates activation of TopBP1 by ATM. Molecular Biology of the Cell, 20 (9). pp. 2351-2360. ISSN 1059-1524. PMCID PMC2675615. https://resolver.caltech.edu/CaltechAUTHORS:20090731-081529374

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Abstract

The activation of ATR-ATRIP in response to double-stranded DNA breaks (DSBs) depends upon ATM in human cells and Xenopus egg extracts. One important aspect of this dependency involves regulation of TopBP1 by ATM. In Xenopus egg extracts, ATM associates with TopBP1 and thereupon phosphorylates it on S1131. This phosphorylation enhances the capacity of TopBP1 to activate the ATR-ATRIP complex. We show that TopBP1 also interacts with the Mre11-Rad50-Nbs1 (MRN) complex in egg extracts in a checkpoint-regulated manner. This interaction involves the Nbs1 subunit of the complex. ATM can no longer interact with TopBP1 in Nbs1-depleted egg extracts, which suggests that the MRN complex helps to bridge ATM and TopBP1 together. The association between TopBP1 and Nbs1 involves the first pair of BRCT repeats in TopBP1. In addition, the two tandem BRCT repeats of Nbs1 are required for this binding. Functional studies with mutated forms of TopBP1 and Nbs1 suggested that the BRCT-dependent association of these proteins is critical for a normal checkpoint response to DSBs. These findings suggest that the MRN complex is a crucial mediator in the process whereby ATM promotes the TopBP1-dependent activation of ATR-ATRIP in response to DSBs.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1091/mbc.E08-12-1190DOIArticle
http://www.molbiolcell.org/cgi/content/abstract/20/9/2351PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675615/PubMed CentralArticle
ORCID:
AuthorORCID
Kumagai, Akiko0000-0003-2422-8053
Dunphy, William G.0000-0001-7598-8939
Additional Information:© 2009 by The American Society for Cell Biology. Under the License and Publishing Agreement, authors grant to the general public, effective two months after publication of (i.e.,. the appearance of) the edited manuscript in an online issue of MBoC, the nonexclusive right to copy, distribute, or display the manuscript subject to the terms of the Creative Commons–Noncommercial–Share Alike 3.0 Unported license (http://creativecommons.org/licenses/by-nc-sa/3.0). Submitted December 10, 2008; Revised February 10, 2009; Accepted March 2, 2009. Monitoring Editor: Daniel J. Lew. We are grateful to J. Ramirez-Lugo and J. DeHart for comments on the manuscript. This work was supported by National Institutes of Health Grants GM043974 and GM070891 to W.G.D.
Funders:
Funding AgencyGrant Number
NIHGM043974
NIHGM070891
Issue or Number:9
PubMed Central ID:PMC2675615
Record Number:CaltechAUTHORS:20090731-081529374
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20090731-081529374
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14746
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:07 Aug 2009 17:23
Last Modified:09 Mar 2020 13:18

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