Mechanisms of oncogene-induced genomic instability.
Mechanisms of oncogene-induced genomic instability.
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DOI：
10.1016/j.bpc.2016.11.008
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发表时间：
2017-06
影响因子：
3.8
通讯作者：
Gonzalo S
中科院分区：
文献类型：
--
作者：
Graziano S;Gonzalo S
癌基因的激活突变促进不受控制的增殖和恶性转化。大约30%的人类癌症携带RAS癌基因突变。矛盾的是，在原代人细胞中表达突变的组成型活性Ras蛋白会导致过早的增殖停滞，即癌基因诱导的衰老（OIS）。这在人类瘤前病变中比在肿瘤病变中更常见，被认为是一种肿瘤抑制机制。衰老细胞仍然具有代谢活性，但处于细胞周期停滞状态，其特征是特定的形态和生理特征，这些特征将它们与增殖细胞和通过其他方式生长停滞的细胞区分开来。虽然OIS建立的分子机制尚不完全清楚，但目前的观点是，人类细胞中的OIS与DNA损伤反应（DDR）途径的持续激活密切相关，这是复制应激的结果。在这里，我们将重点介绍在致癌基因激活时导致超复制应激的分子机制以及复制应激与DDR持续激活之间的串扰的最新进展。我们还将讨论OIS期间DNA修复缺陷的新证据，这可能会增加基因组不稳定性，从而导致衰老绕道和恶性转化。
Activating mutations in oncogenes promote uncontrolled proliferation and malignant transformation. Approximately 30% of human cancers carry mutations in the RAS oncogene. Paradoxically, expression of mutant constitutively active Ras protein in primary human cells results in a premature proliferation arrest known as oncogene-induced senescence (OIS). This is more commonly observed in human pre-neoplasia than in neoplastic lesions, and is considered a tumor suppressor mechanism. Senescent cells are still metabolically active but in a status of cell cycle arrest characterized by specific morphological and physiological features that distinguish them from both proliferating cells, and cells growth-arrested by other means. Although the molecular mechanisms by which OIS is established are not totally understood, the current view is that OIS in human cells is tightly linked to persistent activation of the DNA damage response (DDR) pathway, as a consequence of replication stress. Here we will highlight recent advances in our understanding of molecular mechanisms leading to hyper-replication stress in response to oncogene activation, and of the crosstalk between replication stress and persistent activation of the DDR. We will also discuss new evidence for DNA repair deficiencies during OIS, which might increase the genomic instability that drives senescence bypass and malignant transformation.
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影响因子：
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作者：
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通讯作者：
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64.8
作者：
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通讯作者：
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