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Sokka M, Koalick D, Hemmerich P, Syväoja JE, Pospiech H. The ATR-Activation Domain of TopBP1 Is Required for the Suppression of Origin Firing during the S Phase. International Journal of Molecular Sciences. 2018; 19(8):2376.

The ATR-activation domain of TopBP1 is required for the suppression of origin firing during the S phase

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Author: Sokka, Miiko1,2; Koalick, Dennis3; Hemmerich, Peter3;
Organizations: 1Department of Biology, University of Eastern Finland
2Institute of Biomedicine, University of Eastern Finland
3Leibniz Institute on Aging—Fritz Lipmann Institute
4Faculty of Biochemistry and Molecular Medicine, University of Oulu
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.7 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2018101138086
Language: English
Published: Multidisciplinary Digital Publishing Institute, 2018
Publish Date: 2018-10-11
Description:

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.

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Series: International journal of molecular sciences
ISSN: 1661-6596
ISSN-E: 1422-0067
ISSN-L: 1661-6596
Volume: 19
Issue: 8
Article number: 2376
DOI: 10.3390/ijms19082376
OADOI: https://oadoi.org/10.3390/ijms19082376
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
3111 Biomedicine
Subjects:
ATR
DNA fiber assay
DNA replication
S phase
TopBP1
origin firing
Article
Funding: This research was funded by the Academy of Finland grant 251576 to J.E.S., the Finnish Cultural Foundation, North Carelia Regional fund to M.S., and the UFA Grant 3610S30016 by the German Federal Office for Radiation Protection as part of the “Kompetenzverbund für Strahlenforschung” to H.P. The Fritz Lipmann Institute is a member of the Science Association “Gottfried Wilhelm Leibniz” (WGL) and financially supported by the Federal Government of Germany and the State of Thuringia. Funding for open access charge: Leibniz Insitute on Aging—Fritz Lipmann Institute.
Academy of Finland Grant Number: 251576
Detailed Information: 251576 (Academy of Finland Funding decision)
Dataset Reference: Supplementary material:
  https://www.mdpi.com/1422-0067/19/8/2376/s1
Copyright information: © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
  https://creativecommons.org/licenses/by/4.0/