Chronic oxidative DNA damage due to DNA repair defects causes chromosomal instability in Saccharomyces cerevisiae
Chronic oxidative DNA damage due to DNA repair defects causes chromosomal instability in Saccharomyces cerevisiae
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DOI：
10.1128/mcb.00307-08
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发表时间：
2008-09-01
影响因子：
5.3
通讯作者：
Doetsch, Paul W.
中科院分区：
文献类型：
--
作者：
Degtyareva, Natalya P.;Chen, Lingling;Doetsch, Paul W.
氧化性DNA损伤可能参与癌症的病因学，并被认为通过增加突变率加速肿瘤发生。然而，大多数恶性细胞会获得一种特定类型的基因组不稳定性，其特征是大规模基因组重排，称为染色体不稳定性（CIN）。CIN的分子机制尚未完全了解。我们利用酿酒酵母作为一个模型系统来描绘基因毒性应激和CIN之间的关系。结果发现，在选择性和非选择性生长条件下，慢性、未修复的氧化性DNA损伤水平升高导致染色体畸变的频率非常高。在该系统中，超过细胞适当管理氧化DNA损伤的能力导致“CIN获得”表型，并导致严重的核型不稳定性。这些结果说明了一种新的机制，基因组不稳定，可能是相关的人类致癌。
Oxidative DNA damage is likely to be involved in the etiology of cancer and is thought to accelerate tumorigenesis via increased mutation rates. However, the majority of malignant cells acquire a specific type of genomic instability characterized by large-scale genomic rearrangements, referred to as chromosomal instability (CIN). The molecular mechanisms underlying CIN are not entirely understood. We utilized Saccharomyces cerevisiae as a model system to delineate the relationship between genotoxic stress and CIN. It was found that elevated levels of chronic, unrepaired oxidative DNA damage caused chromosomal aberrations at remarkably high frequencies under both selective and nonselective growth conditions. In this system, exceeding the cellular capacity to appropriately manage oxidative DNA damage resulted in a "gain-of-CIN" phenotype and led to profound karyotypic instability. These results illustrate a novel mechanism for genome destabilization that is likely to be relevant to human carcinogenesis.