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 G2 phases and switches the TopBP1-interacting partner from treslin to E2F1, which results in the termination of replication initiation. Premature activation of Akt in G1 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.

中文翻译：

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Cdk2和Akt对TopBP1的细胞周期依赖性开关功能。

Cdk2依赖的TopBP1-treslin相互作用对于DNA复制启动至关重要。但是，尚不清楚复制启动完成后如何终止此关联。在这里，我们证明了Akt对TopBP1的磷酸化作用与S和G2期中的细胞周期蛋白A激活相吻合，并将与TopBP1相互作用的伴侣从Treslin转变为E2F1，从而终止了复制起始。在G1期过早激活Akt会导致早期转换并抑制DNA复制。TopBP1通常在癌症中过表达，并且可以绕过Cdk2的控制与Treslin相互作用，从而导致DNA复制增强。与此观点一致，降低癌细胞中TopBP1的水平可恢复对Cdk2抑制剂的敏感性。一起，我们的研究通过调节TopBP1-treslin相互作用，将Cdk2和Akt途径与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复制方面起着重要作用。