Cell Cycle-Dependent Switch of TopBP1 Functions by Cdk2 and Akt
Cell Cycle-Dependent Switch of TopBP1 Functions by Cdk2 and Akt
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DOI：
10.1128/mcb.00599-19
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发表时间：
2020-04-01
影响因子：
5.3
通讯作者：
Lin, Weei-Chin
中科院分区：
文献类型：
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作者：
Liu, Kang;Graves, Joshua D.;Lin, Weei-Chin
Cdk2 依赖性 TopBP1-treslin 相互作用对于 DNA 复制起始至关重要。然而，尚不清楚复制启动完成后如何终止这种关联。在此，我们证明 Akt 对 TopBP1 的磷酸化与 S 期和 G(2) 期期间细胞周期蛋白 A 的激活同时发生，并将 TopBP1 相互作用伙伴从 treslin 切换为 E2F1，从而导致复制起始终止。 G(1) 期 Akt 过早激活会导致早期转换并抑制 DNA 复制。 TopBP1 通常在癌症中过度表达，并且可以绕过 Cdk2 的控制与 treslin 相互作用，从而增强 DNA 复制。与这一观点一致，降低癌细胞中 TopBP1 的水平可以恢复对 Cdk2 抑制剂的敏感性。总之，我们的研究通过调节 TopBP1-treslin 相互作用将 Cdk2 和 Akt 通路与 DNA 复制的控制联系起来。这些数据还表明 TopBP1 在驱动癌症中异常 DNA 复制方面发挥着重要作用。
Cdk2-dependent TopBP1-treslin interaction is critical for DNA replication initiation. However, it remains unclear how this association is terminated after replication initiation is finished. Here, we demonstrate that phosphorylation of TopBP1 by Akt coincides with cyclin A activation during S and G(2) phases and switches the TopBP1-interacting partner from treslin to E2F1, which results in the termination of replication initiation. Premature activation of Akt in G(1) phase causes an early switch and inhibits DNA replication. TopBP1 is often overexpressed in cancer and can bypass control by Cdk2 to interact with treslin, leading to enhanced DNA replication. Consistent with this notion, reducing the levels of TopBP1 in cancer cells restores sensitivity to a Cdk2 inhibitor. Together, our study links Cdk2 and Akt pathways to the control of DNA replication through the regulation of TopBP1-treslin interaction. These data also suggest an important role for TopBP1 in driving abnormal DNA replication in cancer.