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Int. J. Mol. Sci. 2018, 19(8), 2376; https://doi.org/10.3390/ijms19082376

The ATR-Activation Domain of TopBP1 Is Required for the Suppression of Origin Firing during the S Phase

1
Department of Biology, University of Eastern Finland, FI-80101 Joensuu, Finland
2
Institute of Biomedicine, University of Eastern Finland, FI-70211 Kuopio, Finland
3
Leibniz Institute on Aging—Fritz Lipmann Institute, DE-07745 Jena, Germany
4
Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014 Oulu, Finland
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
Present address: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
§
Present address: Umweltlabor Rhön-Rennsteig GmbH Marktwasserweg 2, 98617 Meiningen, Germany.
*
Authors to whom correspondence should be addressed.
Received: 22 July 2018 / Revised: 4 August 2018 / Accepted: 6 August 2018 / Published: 13 August 2018
(This article belongs to the Special Issue DNA Replication Stress)
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Abstract

The mammalian DNA replication program is controlled at two phases, the licensing of potential origins of DNA replication in early gap 1 (G1), and the selective firing of a subset of licenced origins in the synthesis (S) phase. Upon entry into the S phase, serine/threonine-protein kinase ATR (ATR) is required for successful completion of the DNA replication program by limiting unnecessary dormant origin activation. Equally important is its activator, DNA topoisomerase 2-binding protein 1 (TopBP1), which is also required for the initiation of DNA replication after a rise in S-phase kinase levels. However, it is unknown how the ATR activation domain of TopBP1 affects DNA replication dynamics. Using human cells conditionally expressing a TopBP1 mutant deficient for ATR activation, we show that functional TopBP1 is required in suppressing local dormant origin activation. Our results demonstrate a regulatory role for TopBP1 in the local balancing of replication fork firing within the S phase. View Full-Text
Keywords: DNA replication; S phase; origin firing; TopBP1; ATR; DNA fiber assay DNA replication; S phase; origin firing; TopBP1; ATR; DNA fiber assay
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Sokka, M.; Koalick, D.; Hemmerich, P.; Syväoja, J.E.; Pospiech, H. The ATR-Activation Domain of TopBP1 Is Required for the Suppression of Origin Firing during the S Phase. Int. J. Mol. Sci. 2018, 19, 2376.

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