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Role for Rif1 in the checkpoint response to damaged DNA in Xenopus egg extracts

Kumar, Sanjay and Yoo, Hae Yong and Kumagai, Akiko and Shevchenko, Anna and Shevchenko, Andrej and Dunphy, William G. (2012) Role for Rif1 in the checkpoint response to damaged DNA in Xenopus egg extracts. Cell Cycle, 11 (6). pp. 1183-1194. ISSN 1538-4101.

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TopBP1 is critical for both DNA replication and checkpoint regulation in vertebrate cells. In this study, we have identified Rif1 as a binding partner of TopBP1 in Xenopus egg extracts. In addition, Rif1 also interacts with both ATM and the Mre11-Rad50-Nbs1 (MRN) complex, which are key regulators of checkpoint responses to double-stranded DNA breaks (DSBs). Depletion of Rif1 from egg extracts compromises the activation of Chk1 in response to DSBs but not stalled replication forks. Removal of Rif1 also has a significant impact on the chromatin-binding behavior of key checkpoint proteins. In particular, binding of TopBP1, ATR and the MRN complex to chromatin containing DSBs is reduced in the absence of Rif1. Rif1 interacts with chromatin in a highly regulated and dynamic manner. In unperturbed egg extracts, the association of Rif1 with chromatin depends upon formation of replication forks. In the presence of DSBs, there is elevated accumulation of Rif1 on chromatin under conditions where the activation of ATM is suppressed. Taken together, these results suggest that Rif1 plays a dynamic role in the early steps of a checkpoint response to DSBs in the egg-extract system by promoting the correct accumulation of key regulators on the DNA.

Item Type:Article
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Kumagai, Akiko0000-0003-2422-8053
Dunphy, William G.0000-0001-7598-8939
Additional Information:© 2012 Landes Bioscience. Submitted: 12/26/11; Accepted: 02/06/12. We are grateful to laboratory members for helpful advice and comments on the manuscript. This work was supported by NIH grants GM043974 and GM070891 and an Ellison Senior Scholar in Aging award to W.G.D.
Funding AgencyGrant Number
Ellison Senior Scholar in Aging awardUNSPECIFIED
Subject Keywords:Rif1, TopBP1, ATR, Chk1, cell cycle control, checkpoint mechanisms, Xenopus egg extract
Issue or Number:6
Record Number:CaltechAUTHORS:20120504-100016725
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:31301
Deposited By: Tony Diaz
Deposited On:08 May 2012 18:55
Last Modified:09 Mar 2020 13:18

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