Department of Biology, University of Eastern Finland, FI-80101 Joensuu, Finland.
Institute of Biomedicine, University of Eastern Finland, FI-70211 Kuopio, Finland.
Int J Mol Sci. 2018 Aug 13;19(8):2376. doi: 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.
哺乳动物的 DNA 复制程序在两个阶段受到控制，即在早期间隙 1（G1）中潜在的 DNA 复制起点的许可，以及在合成（S）期选择性地触发一小部分许可起点的复制。进入 S 期后，丝氨酸/苏氨酸蛋白激酶 ATR（ATR）通过限制不必要的休眠起点激活来确保 DNA 复制程序的成功完成。同样重要的是它的激活剂，DNA 拓扑异构酶 2 结合蛋白 1（TopBP1），它也是在 S 期激酶水平升高后启动 DNA 复制所必需的。然而，ATR 激活结构域的 TopBP1 如何影响 DNA 复制动力学尚不清楚。我们使用人细胞条件性表达一种缺乏 ATR 激活的 TopBP1 突变体，结果表明功能正常的 TopBP1 对于抑制局部休眠起点的激活是必需的。我们的结果表明，TopBP1 在 S 期内复制叉激发的局部平衡中具有调节作用。
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