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首页> 外文期刊>Nature >Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication
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Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication

机译：癌基因诱导的衰老是DNA过度复制引发的DNA损伤反应

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摘要

Early tumorigenesis is associated with the engagement of the DNA-damage checkpoint response(DDR)(1,2). Cell proliferation and transformation induced by oncogene activation are restrained by cellular senescence(3-6). It is unclear whether DDR activation and oncogene-induced senescence (OIS) are causally linked. Here we show that senescence, triggered by the expression of an activated oncogene (H-RasV12) in normal human cells, is a consequence of the activation of a robust DDR. Experimental inactivation of DDR abrogates OIS and promotes cell transformation. DDR and OIS are established after a hyper-replicative phase occurring immediately after oncogene expression. Senescent cells arrest with partly replicated DNA and with DNA replication origins having fired multiple times. In vivo DNA labelling and molecular DNA combing reveal that oncogene activation leads to augmented numbers of active replicons and to alterations in DNA replication fork progression. We also show that oncogene expression does not trigger a DDR in the absence of DNA replication. Last, we show that oncogene activation is associated with DDR activation in a mouse model in vivo. We propose that OIS results from the enforcement of a DDR triggered by oncogene-induced DNA hyper-replication.
机译：早期肿瘤发生与DNA损伤检查点应答（DDR）（1,2）的参与有关。癌基因激活诱导的细胞增殖和转化受到细胞衰老的抑制（3-6）。尚不清楚DDR激活和癌基因诱导的衰老（OIS）是否因果相关。在这里，我们显示衰老是由正常人细胞中激活的致癌基因（H-RasV12）的表达触发的，是鲁棒的DDR激活的结果。 DDR的实验失活消除了OIS并促进了细胞转化。 DDR和OIS在癌基因表达后立即发生的高度复制阶段之后建立。衰老细胞因部分复制的DNA和多次复制的DNA复制起点而停滞。体内DNA标记和分子DNA梳理显示，癌基因激活导致活性复制子数量增加，并导致DNA复制叉进程改变。我们还显示，在没有DNA复制的情况下，癌基因表达不会触发DDR。最后，我们显示癌基因激活与体内小鼠模型中的DDR激活相关。我们认为OIS是由致癌基因诱导的DNA过度复制触发的DDR强制执行导致的。

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