The ATR-Activation Domain of TopBP1 Is Required for the Suppression of Origin Firing during the S Phase
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CitationSokka, Mikko. Koalick, Dennis. Hemmerich, Peter. Syväoja, Juhani E. Pospiech, Helmut. (2018). The ATR-Activation Domain of TopBP1 Is Required for the Suppression of Origin Firing during the S Phase. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 19 (8) , 2376. 10.3390/ijms19082376.
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.