Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, Scotland, UK.
EMBO J. 2010 Sep 1;29(17):2966-78. doi: 10.1038/emboj.2010.171. Epub 2010 Jul 23.
In response to replication stress, Claspin mediates the phosphorylation and activation of Chk1 by ATR. Claspin is not only necessary for the propagation of the DNA-damage signal, but its destruction by the ubiquitin-proteosome pathway is required to allow the cell to continue the cell cycle allowing checkpoint recovery. Here, we demonstrate that both the NF-kappaB family of transcription factors and their upstream kinase IKK can regulate Claspin levels by controlling its mRNA expression. Furthermore, we show that c-Rel directly controls Claspin gene transcription. Disruption of IKK and specific NF-kappaB members impairs ATR-mediated checkpoint function following DNA damage. Importantly, hyperactivation of IKK results in a failure to inactivate Chk1 and impairs the recovery from the DNA checkpoint. These results uncover a novel function for IKK and NF-kappaB modulating the DNA-damage checkpoint response, allowing the cell to integrate different signalling pathways with the DNA-damage response.
针对复制压力，Claspin 通过 ATR 介导 Chk1 的磷酸化和激活。Claspin 不仅是 DNA 损伤信号传播所必需的，而且其通过泛素蛋白酶体途径的破坏对于细胞继续细胞周期并允许检查点恢复也是必需的。在这里，我们证明 NF-κB 转录因子家族及其上游激酶 IKK 可以通过控制其 mRNA 表达来调节 Claspin 的水平。此外，我们表明 c-Rel 可以直接控制 Claspin 基因的转录。IKK 和特定 NF-κB 成员的破坏会损害 DNA 损伤后 ATR 介导的检查点功能。重要的是，IKK 的过度激活会导致 Chk1 无法失活，并损害 DNA 检查点的恢复。这些结果揭示了 IKK 和 NF-κB 调节 DNA 损伤检查点反应的新功能，使细胞能够将不同的信号通路与 DNA 损伤反应整合在一起。
