Combined haploinsufficiency for ATM and RAD9 as a factor in cell transformation, apoptosis, and DNA lesion repair dynamics.
Combined haploinsufficiency for ATM and RAD9 as a factor in cell transformation, apoptosis, and DNA lesion repair dynamics.
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DOI：
10.1158/0008-5472.933.65.3
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发表时间：
2005-02
期刊：
影响因子：
11.2
通讯作者：
L. Smilenov;H. Lieberman;S. Mitchell;R. A. Baker;K. M. Hopkins;E. Hall
中科院分区：
文献类型：
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作者：
L. Smilenov;H. Lieberman;S. Mitchell;R. A. Baker;K. M. Hopkins;E. Hall
癌基因、肿瘤抑制基因和DNA损伤处理基因的功能丧失与许多类型癌症的发展有关，但对于绝大多数病例，与特定的生殖系突变没有联系。在过去的几年中，杂合性导致参与DNA修复途径的蛋白质的单倍不足被证明在DNA损伤诱导后的基因组不稳定性和致癌性中起作用。由于单倍不足对一种蛋白质的影响相对较小，我们假设癌症易感性可能是两个或多个基因杂合性的加和效应的结果，这对控制DNA损伤信号传导、修复或凋亡的途径至关重要。为了解决这个问题，研究了与DNA损伤的细胞反应相关的一种或两种蛋白质ATM和RAD 9单倍不足的原代小鼠细胞。结果表明，具有低水平的ATM和RAD 9蛋白质的细胞对辐射转化更敏感，具有不同的DNA双链断裂修复动力学，并且与野生型对照或仅对这些蛋白质之一单倍不足的那些细胞相比，凋亡较少。我们的结论是，在应激条件下，ATM/RAD 9细胞信号网络介导的DNA修复的效率和能力取决于这两种蛋白质的丰度，并且一般来说，DNA修复网络效率是基因型依赖性的，并且可以在特定范围内变化。
Loss of function of oncogenes, tumor suppressor genes and DNA damage processing genes has been implicated in the development of many types of cancer, but for the vast majority of cases, there is no link to specific germ line mutations. In the last several years, heterozygosity leading to haploinsufficiency for proteins involved in DNA repair pathways was shown to play a role in genomic instability and carcinogenesis after DNA damage is induced. Because the effect of haploinsufficiency for one protein is relatively small, we hypothesize that predisposition to cancer could be a result of the additive effect of heterozygosity for two or more genes, critical for pathways that control DNA damage signaling, repair or apoptosis. To address this issue, primary mouse cells, haploinsufficient for one or two proteins, ATM and RAD9, related to the cellular response to DNA damage were examined. The results show that cells having low levels of both ATM and RAD9 proteins are more sensitive to transformation by radiation, have different DNA double-strand break repair dynamics and are less apoptotic when compared with wild-type controls or those cells haploinsufficient for only one of these proteins. Our conclusions are that under stress conditions, the efficiency and capacity for DNA repair mediated by the ATM/RAD9 cell signaling network depend on the abundance of both proteins and that, in general, DNA repair network efficiencies are genotype-dependent and can vary within a specific range.