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首页> 外文期刊>Nature >Endonuclease-independent LINE-1 retrotransposition at mammalian telomeres
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Endonuclease-independent LINE-1 retrotransposition at mammalian telomeres

机译：哺乳动物端粒独立于核酸内切酶的LINE-1逆转座子

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摘要

Long interspersed element-1 (LINE-1 or L1) elements are abundant, non-long-terminal-repeat (non-LTR) retrotransposons that comprise ～17% of human DNA. The average human genome contains ～80-100 retrotransposition-competent L1s (ref. 2), and they mobilize by a process that uses both the L1 endonuclease and reverse transcriptase, termed target-site primed reverse transcription. We have previously reported an efficient, endonuclease-independent L1 retrotransposition pathway (EN_i) in certain Chinese hamster ovary (CHO) cell lines that are defective in the non-homologous end-joining (NHEJ) pathway of DNA double-strand-break repair. Here we have characterized EN_i retrotransposition events generated in V3 CHO cells, which are deficient in DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity and have both dysfunctional telomeres and an NHEJ defect. Notably, ～30% of EN_i retrotransposition events insert in an orientation-specific manner adjacent to a perfect telomere repeat (5'-TTAGGG-3'). Similar insertions were not detected among EN_i retrotransposition events generated in controls or in XR-1 CHO cells deficient for XRCC4, an NHEJ factor that is required for DNA ligation but has no known function in telomere maintenance. Furthermore, transient expression of a dominant-negative allele of human TRF2 (also called TERF2) in XRCC4-deficient XR-1 cells, which disrupts telomere capping, enables telomere-associated EN_i retrotransposition events. These data indicate that L1s containing a disabled endonuclease can use dysfunctional telomeres as an integration substrate. The findings highlight similarities between the mechanism of EN_i retrotransposition and the action of telomerase, because both processes can use a 3' OH for priming reverse transcription at either internal DNA lesions or chromosome ends. Thus, we propose that EN_i retrotransposition is an ancestral mechanism of RNA-mediated DNA repair associated with non-LTR retrotransposons that may have been used before the acquisition of an endonuclease domain.
机译：长时间散布的element-1（LINE-1或L1）元件是丰富的非长末端重复（non-LTR）逆转座子，占人类DNA的约17％。人类平均每个基因组包含约80-100个具有逆转录作用的L1（参考文献2），它们通过使用L1核酸内切酶和逆转录酶（称为靶位点引发的逆转录）的过程进行动员。我们以前已经报道了在某些中国仓鼠卵巢（CHO）细胞系中有效的，独立于核酸内切酶的L1逆转录转位途径（EN_i），该细胞系在DNA双链断裂修复的非同源末端连接（NHEJ）途径中存在缺陷。在这里，我们已经表征了在V3 CHO细胞中产生的EN_i逆转位事件，这些事件缺乏DNA依赖性蛋白激酶催化亚基（DNA-PKcs）活性，并且具有功能异常的端粒和NHEJ缺陷。值得注意的是，约30％的EN_i逆转座事件以特定于方向的方式插入完美的端粒重复序列（5'-TTAGGG-3'）。在对照或缺乏XRCC4的XR-1 CHO细胞中产生的EN_i逆转位事件中未检测到类似的插入，XRCC4是DNA连接所必需的NHEJ因子，但在端粒维持中没有已知的功能。此外，人TRF2（也称为TERF2）的显性阴性等位基因在XRCC4缺陷型XR-1细胞中的瞬时表达会破坏端粒的加帽，从而使端粒相关的EN_i逆转录事件得以发生。这些数据表明，含有失活的核酸内切酶的L1可以使用功能异常的端粒作为整合底物。这些发现突显了EN_i逆转座机制与端粒酶作用之间的相似性，因为这两个过程都可以使用3'OH在内部DNA损伤或染色体末端引发逆转录。因此，我们提出EN_i逆转座是RNA介导的DNA修复与非LTR逆转座子相关的祖先机制，在获得内切核酸酶结构域之前可能已经使用过。

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