Chemotherapeutically induced deletion of expanded triplet repeats
Chemotherapeutically induced deletion of expanded triplet repeats
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DOI：
10.1016/s0027-5107(02)00190-2
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发表时间：
2002-10-31
影响因子：
2.3
通讯作者：
Sinden, RR
中科院分区：
文献类型：
--
作者：
Hashem, VI;Sinden, RR
与DNA重复序列扩增相关的神经退行性疾病的数量目前约为18种，随着这种新型突变引起的其他疾病的鉴定，这种疾病的数量继续增加。通常，扩展的重复序列在代际传播时偏向于进一步扩展，并且疾病症状显示出随着三联体重复序列道的长度增加而更早的发病年龄和更严重的程度。大多数疾病表现出进行性神经和/或肌肉退化，可导致完全残疾和死亡。到目前为止，还没有治疗任何重复疾病的遗传基础。鉴于这些疾病的严重程度与重复序列长度有关，减少重复序列长度可能会延迟发病并降低疾病严重程度。在这里，我们测试的假设，即引入损伤DNA，这导致随后的修复事件，可以导致重复缺失率增加。在大肠杆菌中应用敏感的遗传测定[Mut. Res. 502（2002）25]，我们证明了某些DNA损伤剂，包括EMS、ENU、UV光和抗癌剂丝裂霉素C、顺铂和X射线增加（CTG）的缺失速率。(CAG)以长度和方向依赖的方式重复。此外，对DNA的氧化损伤也会增加重复序列的缺失率。这些结果表明，减少三联体重复长度的化疗方法可能提供一种可能的理由来减缓，停止或逆转这些疾病的进展。(C)2002 Elsevier Science B. V.保留所有权利。
The number of neurodegenerative disorders associated with the expansion of DNA repeats, currently about 18, continues to increase as additional diseases caused by this novel type of mutation are identified. Typically, expanded repeats are biased toward further expansion upon intergenerational transmission, and disease symptoms show an earlier age of onset and greater severity as the length of the triplet repeat tract increases. Most diseases exhibit progressive neurological and/or muscular degeneration that can lead to total disability and death. As yet, no treatment exists for the genetic basis of any repeat disease. Given that the severity of these diseases is related to repeat tract length, reducing repeat lengths might delay the onset and reduce disease severity. Here, we test the hypothesis that the introduction of damage into DNA, which results in subsequent repair events, can lead to an increased rate of repeat deletion. Applying a sensitive genetic assay in Escherichia coli [Mut. Res. 502 (2002) 25], we demonstrate that certain DNA damaging agents, including EMS, ENU, UV light, and anticancer agents mitomycin C, cisplatin, and X-rays increase the rate of deletion of (CTG).(CAG) repeats in a length and orientation dependent fashion. In addition, oxidative damage to DNA also increases the deletion rate of repeats. These results suggest that a chemotherapeutic approach to the reduction in triplet repeat length may provide one possible rationale to slow, stop, or reverse the progression of these diseases. (C) 2002 Elsevier Science B.V. All rights reserved.