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doi:10.1083/jcb.200810185
The Journal of Cell Biology
The Rockefeller University Press, 0021-9525 $30.00
© Yan et al.
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ARTICLE

TopBP1 and DNA polymerase-{alpha} directly recruit the 9-1-1 complex to stalled DNA replication forks



Shan Yan and W. Matthew Michael

The Biological Laboratories, Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138

Correspondence to W. Matthew Michael: mmichael{at}fas.harvard.edu

TopBP1 and the Rad9–Rad1–Hus1 (9-1-1) complex activate the ataxia telangiectasia mutated and Rad3-related (ATR) protein kinase at stalled replication forks. ATR is recruited to stalled forks through its binding partner, ATR-interacting protein (ATRIP); however, it is unclear how TopBP1 and 9-1-1 are recruited so that they may join ATR–ATRIP and initiate signaling. In this study, we use Xenopus laevis egg extracts to determine the requirements for 9-1-1 loading. We show that TopBP1 is required for the recruitment of both 9-1-1 and DNA polymerase (pol)-{alpha} to sites of replication stress. Furthermore, we show that pol-{alpha} is also directly required for Rad9 loading. Our study identifies an assembly pathway, which is controlled by TopBP1 and includes pol-{alpha}, that mediates the loading of the 9-1-1 complex onto stalled replication forks. These findings clarify early events in the assembly of checkpoint signaling complexes on DNA and identify TopBP1 as a critical sensor of replication stress.

© 2009 Yan and Michael This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

Abbreviations used in this paper: ATR, ataxia telangiectasia mutated and Rad3 related; ATRIP, ATR-interacting protein; BRCT, BRCA1 C terminus; ELB, egg lysis buffer; IVT, in vitro transcription/translation; PCNA, proliferating cell nuclear antigen; pol, polymerase; RFC, replication factor C; RPA, replication protein A; ssDNA, single-stranded DNA; WT, wild type.


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