Induction of genome instability by DNA damage in Saccharomyces cerevisiae
Induction of genome instability by DNA damage in Saccharomyces cerevisiae
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DOI：
10.1016/s1568-7864(02)00216-1
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发表时间：
2003-03-01
期刊：
影响因子：
3.8
通讯作者：
Kolodner, RD
中科院分区：
文献类型：
--
作者：
Myung, K;Kolodner, RD
总染色体重排（GCR）的积累是许多类型癌细胞的特征，尽管尚不清楚是什么缺陷导致这些重排以及观察到的不同类型的GCR是如何形成的。在本研究中，我们使用了酿酒酵母系统测量GCR分析各种DNA损伤剂诱导GCR的能力。观察到的两种最有效的GCR诱导剂是甲基甲磺酸酯（MMS）和HO-核酸内切酶诱导的双链断裂（DSB）。博来霉素、喜树碱和γ-照射诱导中等水平的GCR，顺铂诱导非常低水平的GCR，而N-甲基-N' -硝基-N-亚硝基胍（MNNG）和甲磺酸乙酯（EMS）主要诱导碱基取代突变。MMS处理主要诱导重排，其中染色体的末端被删除并且添加新的端粒（端粒添加），并且还诱导易位。与此GCR谱一致，MMS诱导的GCR的形成主要依赖于端粒维持功能，并且在端粒维持功能和非同源末端连接（NHEJ）都有缺陷的突变体中完全消除。相比之下，HO-核酸内切酶DSB主要诱导易位和间质缺失，而很少观察到端粒添加。遗传学分析表明，HODSB诱导的GCR受到许多途径的抑制，包括DNA损伤检查点，DSB修复途径和N-HEJ。(C)2002 Elsevier Science B. V.保留所有权利。
The accumulation of gross chromosomal rearrangements (GCRs) is a characteristic of many types of cancer cells, although it is unclear what defects cause these rearrangements and how the different types of GCRs observed are formed. In the present study, we have used a Saccharomyces cerevisiae system for measuring GCRs to analyze the ability of a variety of DNA damaging agents to induce GCRs. The two most potent inducers of GCRs observed were methyl methane sulfonate (MMS) and HO-endonuclease-induced double strand breaks (DSBs). Bleomycin, camptothecan and gamma-irradiation induced intermediate levels of GCRs and cisplatin induced very low levels of GCRs whereas N-methyl-N' -nitro-N-nitrosoguanidine (MNNG) and ethyl methane sulfonate (EMS) primarily induced base substitution mutations. MMS treatment primarily induced rearrangements in which the end of a chromosome was deleted and a new telomere was added (telomere additions) and also induced translocations. Consistent with this GCR spectrum, the formation of MMS-induced GCRs was primarily dependent on telomere maintenance functions and were completely eliminated in mutants that were defective for both telomere maintenance functions and non-homologous end joining (NHEJ). In contrast, HO-endonuclease DSBs induced mostly translocations and interstitial deletions whereas few telomere additions were observed. Genetic analysis indicated that HO DSB-induced GCRs were suppressed by a number of pathways including the DNA damage checkpoints, DSB repair pathways and N-HEJ. (C) 2002 Elsevier Science B.V. All rights reserved.