Alterations in DNA repair gene expression under hypoxia -: Elucidating the mechanisms of hypoxia-induced genetic instability
Alterations in DNA repair gene expression under hypoxia -: Elucidating the mechanisms of hypoxia-induced genetic instability
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DOI：
10.1196/annals.1339.049
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发表时间：
2005-01-01
期刊：
影响因子：
--
通讯作者：
Glazer, PM
中科院分区：
文献类型：
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作者：
Bindra, RS;Schaffer, PJ;Glazer, PM
缺氧是实体瘤的共同特征，与遗传不稳定性和肿瘤进展有关。先前的研究表明，DNA修复基因在缺氧胁迫下表达的改变可能是这种遗传不稳定性的一部分原因。在这里，我们证明了RAD51的表达，同源重组（HR）的关键介质，在来自广泛组织的许多细胞系中受到缺氧的抑制。缺氧对该基因的抑制以细胞周期和缺氧诱导因子（HIF）独立的方式发生，并且观察到在缺氧后持续降低RAD51的表达。Rad51也降低。表达与缺氧和缺氧后细胞HR修复功能损伤相关。基于这些数据，我们提出了一种新的机制，即通过抑制肿瘤微环境中癌细胞的HR通路，缺氧诱导遗传不稳定。
Hypoxia is a common feature of solid tumors and is associated with genetic instability and tumor progression. It has been shown previously that alterations in the expression of DNA repair genes in response to hypoxic stress may account for a proportion of such genetic instability. Here, we demonstrate that the expression of RAD51, a critical mediator of homologous recombination (HR), is repressed by hypoxia in numerous cell lines derived from a wide range of tissues. Repression of this gene by hypoxia occurs in a cell cycle- and hypoxia-inducible factor (HIF)-independent manner, and decreased RAD51 expression was observed to persist during the post-hypoxic period. In addition, decreases in Rad51. expression were correlated with functional impairments in HR repair in hypoxic and post-hypoxic cells. Based on these data, we propose a novel mechanism of hypoxia-induced genetic instability via suppression of the HR pathway in cancer cells within the tumor microenvironment.