Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication
Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication
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DOI：
10.1038/nature05327
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发表时间：
2006-11-30
期刊：
影响因子：
64.8
通讯作者：
di Fagagna, Fabrizio d'Adda
中科院分区：
文献类型：
--
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
早期肿瘤发生与DNA损伤检查点反应（DDR）的参与有关（1，2）。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）。目前还不清楚DDR激活和癌基因诱导的衰老（OIS）是否存在因果关系。在这里，我们表明，衰老，在正常人体细胞中激活的癌基因（H-RasV 12）的表达触发，是一个强大的DDR激活的结果。DDR的实验性失活消除了OIS并促进细胞转化。DDR和OIS在癌基因表达后立即发生的超复制期后建立。衰老细胞停滞与部分复制的DNA和DNA复制起点已多次发射。体内DNA标记和分子DNA梳理揭示，癌基因激活导致活性复制子的数量增加和DNA复制叉进展的改变。我们还表明，癌基因的表达不会触发DDR的DNA复制的情况下。最后，我们表明，癌基因激活与DDR激活在体内小鼠模型。我们认为OIS是由癌基因诱导的DNA超复制引发的DDR的执行导致的。
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.