Mobile genetic element activation and genotoxic cancer therapy: potential clinical implications.
Mobile genetic element activation and genotoxic cancer therapy: potential clinical implications.
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DOI：
10.2165/00129785-200202010-00003
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发表时间：
2002-01-01
期刊：
影响因子：
--
通讯作者：
Rudin, Charles M
中科院分区：
文献类型：
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作者：
Hagan, Christy R;Rudin, Charles M
大约四分之一的人类基因组是由短和长穿插的元素（分别是sin和LINEs）组成的。这些元件通过一个称为逆转录转位的过程在基因组中传播，这个过程包括将一个元件转录成RNA，反转录成cDNA，然后将复制的元件重新插入到新的基因组位置。涉及这些元件的重组事件，包括新插入活性基因，与许多人类疾病有关。尽管这些元素已经在基因组中复制了数十万份拷贝，但在大多数情况下，它们在转录上保持沉默，因此不会主动复制。基因组中控制逆转录转座因子激活的信号尚未被定义。我们的实验室最近发现，细胞暴露于各种dna损伤剂，包括几种常见的化疗药物和γ辐射，与SINE转录的显著诱导以及伴随的内源性逆转录酶活性有关。由于SINEs不编码逆转录酶，后一项发现表明，在DNA损伤的反应中，逆转录转座因子的激活更为全面。总之，这些观察结果表明，基因毒性暴露不仅可以通过直接DNA损伤，还可以通过间接激活基因组中潜在的致突变移动元件导致基因组突变。人类基因组中反转录转座因子的非随机分布可能有助于暴露于遗传毒性药物的患者继发性恶性肿瘤相关的特征性易位事件的模式。在这里，我们描述了逆转录转座因子可能导致疾病的这些机制和其他机制，并概述了对基因组中这一大部分未被探索的大片段的了解。了解细胞对基因毒性应激的反应可能有助于预测癌症治疗后继发恶性肿瘤的风险和预防。
Approximately one-quarter of the human genome is composed of short and long interspersed elements (SINEs and LINEs, respectively). These elements have spread throughout the genome by a process termed retrotransposition, consisting of transcription of an element into RNA, reverse transcription into cDNA, and reinsertion of the copied element into a new genomic location. Recombination events involving these elements, including novel insertions into active genes, have been associated with a number of human diseases. Despite the fact that these elements have replicated to hundreds of thousands of copies in the genome, under most conditions they remain transcriptionally silent, and therefore are not actively replicating. The signals controlling retrotransposable element activation in the genome have not been defined. Our laboratory recently found that exposure of cells to a variety of DNA-damaging agents, including several common chemotherapeutic drugs and gamma-radiation, is associated with dramatic induction of SINE transcription, and of a concomitant endogenous reverse transcriptase activity. As SINEs do not encode for reverse transcriptase, the latter finding suggests a more global activation of retrotransposable elements in response to DNA damage. Together these observations suggest that genotoxic exposure may lead to genomic mutation not only through direct DNA damage, but also through indirect activation of potentially mutagenic mobile elements in the genome. The nonrandom distribution of retrotransposable elements in the human genome may contribute to the pattern of characteristic translocation events associated with secondary malignancies in patients exposed to genotoxic agents. Here we describe these and other mechanisms by which retrotransposable elements can contribute to disease, and present an overview of what is known about this large, and largely unexplored, segment of the genome. Understanding the cellular responses to genotoxic stress may permit the development of a means of predicting the risks and preventing the development of secondary malignancy following cancer therapy.