Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints
Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints
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DOI：
10.1038/nature05268
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发表时间：
2006-11-30
期刊：
影响因子：
64.8
通讯作者：
Gorgoulis, Vassilis G.
中科院分区：
文献类型：
--
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
最近的研究表明，肿瘤发生障碍的存在可以减缓或抑制肿瘤前病变向瘤变的进展。其中一种屏障涉及DNA复制应激，它导致DNA损伤检查点的激活，从而导致细胞凋亡或细胞周期停滞（1,2），而第二种屏障是由癌基因诱导的衰老介导的（3-6）。这两个障碍之间的关系，如果有的话，还没有被阐明。在这里，我们表明癌基因诱导的衰老与DNA复制应激的迹象有关，包括过早终止的DNA复制分叉和DNA双链断裂。抑制DNA双链断裂反应激酶ataxia毛细血管扩张突变（ATM）抑制衰老的诱导，并在小鼠模型中导致肿瘤大小和侵袭性增加。对人类癌前病变的分析进一步表明，DNA损伤和衰老标记密切相关。因此，人类肿瘤前病变的衰老是癌基因诱导的DNA复制应激的一种表现，与细胞凋亡一起，为恶性进展提供了屏障。
Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest(1,2), whereas a second barrier is mediated by oncogene-induced senescence(3-6). The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.