The mRNA surveillance protein hSMG-1 functions in genotoxic stress response pathways in mammalian cells
The mRNA surveillance protein hSMG-1 functions in genotoxic stress response pathways in mammalian cells
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DOI：
10.1016/j.molcel.2004.05.005
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发表时间：
2004-06-04
期刊：
影响因子：
16
通讯作者：
Abraham, RT
中科院分区：
文献类型：
--
作者：
Brumbaugh, KM;Otterness, DM;Abraham, RT
PI 3-激酶相关激酶（PIKK）家族成员在真核细胞中的促有丝分裂和应激诱导的信号传导途径中起作用。在这里，我们的特点是最新的PIKK家族成员，hSMG-1，作为一种遗传毒性的应激激活蛋白激酶，显示一些功能重叠的相关激酶，ATM，在人类细胞。ATM和hSMG-1都磷酸化检查点蛋白p53和无义介导的mRNA衰变（NMD）蛋白hUpf 1中含有Ser/Thr-Gln的靶序列。在细胞暴露于遗传毒性应激后，hSMG-1的表达是最佳p53活化所必需的，并且hSMG-1的耗尽导致自发DNA损伤和对电离辐射（IR）的敏感性增加。此外，IR暴露触发hUpf 1在Ser/Thr-Gln基序的磷酸化，ATM和hSMG-1都有助于这些磷酸化事件。最后，NMD在hSMG-1缺陷细胞中被抑制，但在ATM缺陷细胞中不被抑制。这些结果表明，hSMG-1在维持人类细胞基因组和转录组完整性方面发挥重要作用。
Members of the PI3-kinase-related kinase (PIKK) family function in mitogenic and stress-induced signaling pathways in eukaryotic cells. Here, we characterize the newest PIKK family member, hSMG-1, as a genotoxic stress-activated protein kinase that displays some functional overlap with the related kinase, ATM, in human cells. Both ATM and hSMG-1 phosphorylate Ser/Thr-Gin-containing target sequences in the checkpoint protein p53 and the nonsense-mediated mRNA decay (NMD) protein hUpf1. Expression of hSMG-1 is required for optimal p53 activation after cellular exposure to genotoxic stress, and depletion of hSMG-1 leads to spontaneous DNA damage and increased sensitivity to ionizing radiation (IR). Moreover, IR exposure triggers hUpf1 phosphorylation at Ser/Thr-Gln motifs, and both ATM and hSMG-1 contribute to these phosphorylation events. Finally, NMD is suppressed in hSMG-1- but not ATM-deficient cells. These results indicate that hSMG-1 plays important roles in the maintenance of both genome and transcriptome integrity in human cells.