Inviting instability: Transposable elements, double-strand breaks, and the maintenance of genome integrity
Inviting instability: Transposable elements, double-strand breaks, and the maintenance of genome integrity
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DOI：
10.1016/j.mrfmmm.2006.11.021
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发表时间：
2007-03-01
影响因子：
2.3
通讯作者：
Deininger, P. L.
中科院分区：
文献类型：
--
作者：
Hedges, D. J.;Deininger, P. L.
哺乳动物基因组中普遍存在的移动元件对维持基因组完整性提出了相当大的挑战。移动元件参与基因组重排的倾向很大程度上是它们散布的同源性的结果。作为非等位基因序列同源性的区域，它们有可能在减数分裂重组和 DNA 修复过程中以破坏性方式相互作用，导致从删除和重复到大规模染色体重排的基因组改变。尽管转座元件（TE）插入事件的有害影响已被广泛记录，但可以说，通过插入后基因组的不稳定性，它们对宿主基因组构成了最大的危害。尽管重要的进化创新会定期产生，但涉及 TE 序列的基因组改变本质上更常见的是中性或有害的。 TE 介导的重排可能导致超过 25 种人类遗传疾病，这或许可以最好地说明这种不稳定性的潜在负面后果。其中一些重排，例如涉及白血病中的 MLL 基因座和家族性高胆固醇血症中的 LDL 受体的重排，代表了在人类群体中多次独立出现的复发突变。虽然 TE 不稳定性是塑造真核基因组的强大力量，也是遗传疾病的重要来源，但控制这些事件的频率和多样性的机制仍有待澄清。在这里，我们调查了有关哺乳动物基于移动元件的遗传不稳定性的机制的当前知识状况。与更简单的真核系统相比，哺乳动物细胞的 DNA 修复整体似乎有一些修改，使它们能够更好地应对 TE 产生的大量散布同源性。除了非等位基因序列同源性的破坏潜力之外，我们还考虑了最近的证据，表明 TE 的核酸内切酶产物也可能在引发哺乳动物基因组不稳定中发挥关键作用。 (c) 2006 Elsevier B.V. 保留所有权利。
The ubiquity of mobile elements in mammalian genomes poses considerable challenges for the maintenance of genome integrity. The predisposition of mobile elements towards participation in genomic rearrangements is largely a consequence of their interspersed homologous nature. As tracts of nonallelic sequence homology, they have the potential to interact in a disruptive manner during both meiotic recombination and DNA repair processes, resulting in genomic alterations ranging from deletions and duplications to large-scale chromosomal rearrangements. Although the deleterious effects of transposable element (TE) insertion events have been extensively documented, it is arguably through post-insertion genomic instability that they pose the greatest hazard to their host genomes. Despite the periodic generation of important evolutionary innovations, genomic alterations involving TE sequences are far more frequently neutral or deleterious in nature. The potentially negative consequences of this instability are perhaps best illustrated by the > 25 human genetic diseases that are attributable to TE-mediated rearrangements. Some of these rearrangements, such as those involving the MLL locus in leukemia and the LDL receptor in familial hypercholesterolemia, represent recurrent mutations that have independently arisen multiple times in human populations.While TE-instability has been a potent force in shaping eukaryotic genomes and a significant source of genetic disease, much conceming the mechanisms governing the frequency and variety of these events remains to be clarified. Here we survey the current state of knowledge regarding the mechanisms underlying mobile element-based genetic instability in mammals. Compared to simpler eukaryotic systems, mammalian cells appear to have several modifications to their DNA-repair ensemble that allow them to better cope with the large amount of interspersed homology that has been generated by TEs. In addition to the disruptive potential of nonallelic sequence homology, we also consider recent evidence suggesting that the endonuclease products of TEs may also play a key role in instigating mammalian genorme instability. (c) 2006 Elsevier B.V. All rights reserved.