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Nucleic Acids Research Advance Access published online on January 12, 2009
Nucleic Acids Research, doi:10.1093/nar/gkn1075
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genome integrity, repair and replication

Cooperative activation of the ATR checkpoint kinase by TopBP1 and damaged DNA

Jun-Hyuk Choi, Laura A. Lindsey-Boltz and Aziz Sancar*

Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7260, USA

*To whom correspondence should be addressed. Tel: +1 919 962 0115; Fax: +1 919 966 2852; Email: aziz_sancar{at}med.unc.edu

Received November 20, 2008. Revised December 18, 2008. Accepted December 21, 2008.

TopBP1, acting in concert with DNA containing bulky base lesions, stimulates ATR kinase activity under physiologically relevant reaction conditions. Here, we analyze the roles of the three components in ATR activation: DNA, base damage and TopBP1. We show that base adducts caused by a potent carcinogen, benzo[a]pyrene diol epoxide (BPDE), constitute a strong signal for TopBP1-dependent ATR kinase activity on Chk1 and p53. We find that the C-terminus of TopBP1 binds preferentially to damaged DNA and is sufficient to mediate damaged DNA-dependent ATR activation in a manner similar to full-length TopBP1. Significantly, we find that stimulation of ATR by BPDE-damaged DNA exhibits strong dependence on the length of DNA, with essentially no stimulation with fragments of 0.2 kb and reaching maximum stimulation with 2 kb fragments. Moreover, TopBP1 shows preferential binding to longer DNA fragments and, in contrast to previous biochemical studies, TopBP1 binding is completely independent of DNA ends. We find that TopBP1 binds to circular and linear DNAs with comparable affinities and that these DNA forms elicit the same level of TopBP1-dependent ATR activation. Taken together, these findings suggest a cooperative activation mechanism for the ATR checkpoint kinase by TopBP1 and damaged DNA.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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L. A. Lindsey-Boltz, O. Sercin, J.-H. Choi, and A. Sancar
Reconstitution of Human Claspin-mediated Phosphorylation of Chk1 by the ATR (Ataxia Telangiectasia-mutated and Rad3-related) Checkpoint Kinase
J. Biol. Chem., November 27, 2009; 284(48): 33107 - 33114.
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