The ATR-activation domain of TopBP1 is required for the suppression of origin firing during the S phase
Sokka, Miiko; Koalick, Dennis; Hemmerich, Peter; Syväoja, Juhani E.; Pospiech, Helmut (2018-08-13)
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.
© 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/).
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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