DNA double-strand breaks: signaling, repair and the cancer connection
DNA double-strand breaks: signaling, repair and the cancer connection
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DOI：
10.1038/85798
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发表时间：
2001-03-01
期刊：
影响因子：
30.8
通讯作者：
Jackson, SP
中科院分区：
文献类型：
--
作者：
Khanna, KK;Jackson, SP
为了确保遗传信息的高保真传输，细胞已经进化出监测基因组完整性的机制。细胞对DNA损伤的反应是通过激活复杂的DNA损伤反应途径来实现的，该途径包括细胞周期停滞、部分基因的转录和转录后激活，包括那些与DNA修复相关的基因，在某些情况下，还会触发细胞程序性死亡。不能对DNA损伤做出适当的反应或修复会导致遗传不稳定，这反过来可能会提高癌症的发展速度。事实上，越来越清楚的是，DNA损伤信号和修复途径的缺陷是大多数(如果不是全部)人类癌症的根本原因。在这里，我们描述了在我们的理解的最新进展，细胞如何检测和信号的存在和修复的一种特别重要的形式的DNA损伤的电离辐射-DNA双链断裂(DSB)。此外，我们还讨论了肿瘤抑制蛋白如P53、ATM、BRCA1和BRCA2是如何与这些途径联系在一起的，以及越来越多的证据是如何将细胞对DNA双链断裂的反应缺陷与肿瘤发生联系起来的。
To ensure the high-fidelity transmission of genetic information, cells have evolved mechanisms to monitor genome integrity. Cells respond to DNA damage by activating a complex DNA-damage-response pathway that includes cell-cycle arrest, the transcriptional and post-transcriptional activation of a subset of genes including those associated with DNA repair, and, under some circumstances, the triggering of programmed cell death. An inability to respond properly to, or to repair, DNA damage leads to genetic instability, which in turn may enhance the rate of cancer development. Indeed, it is becoming increasingly clear that deficiencies in DNA-damage signaling and repair pathways are fundamental to the etiology of most, if not all, human cancers. Here we describe recent progress in our understanding of how cells detect and signal the presence and repair of one particularly important form of DNA damage induced by ionizing radiation-the DNA double-strand break (DSB). Moreover, we discuss how tumor suppressor proteins such as p53, ATM, Brca1 and Brca2 have been linked to such pathways, and how accumulating evidence is connecting deficiencies in cellular responses to DNA DSBs with tumorigenesis.