Ataxia telangiectasia mutated (ATM) modulates long interspersed element-1 (L1) retrotransposition in human neural stem cells
Ataxia telangiectasia mutated (ATM) modulates long interspersed element-1 (L1) retrotransposition in human neural stem cells
复制标题
DOI：
10.1073/pnas.1100273108
复制
发表时间：
2011-12-20
影响因子：
11.1
通讯作者：
Gage, Fred H.
中科院分区：
文献类型：
--
作者：
Coufal, Nicole G.;Luis Garcia-Perez, Jose;Gage, Fred H.
长穿插元件-1 （L1）反转录转座子占哺乳动物基因组的20%，持续的L1反转录转座子事件可以通过各种机制影响遗传多样性。先前的研究表明，内源性L1逆转录可发生在种系和早期胚胎发育过程中。此外，最近的数据表明，工程人类L1可以在人类神经祖细胞中进行体细胞逆转录，并且在正常对照者以及Rett综合征患者的大脑中可以检测到人类特异性L1 DNA含量的增加。在这里，我们证明了在缺乏或含有严重降低水平的失调性毛细血管扩张突变（一种丝氨酸/苏氨酸激酶参与DNA损伤信号传导和神经退行性疾病）的细胞中，工程人类L1s的反转录效率增加。我们证明，在共济失调毛细血管扩张突变缺陷细胞中，L1逆转录的增加很可能是通过传统的靶位引物逆转录发生的，并且每个细胞产生更长或更多的L1逆转录事件。最后，我们提供的证据表明，与健康对照相比，共济失调毛细血管扩张患者死后脑组织中人类特异性L1 DNA拷贝数增加。总之，这些数据表明，参与DNA损伤反应的细胞蛋白可能调节L1反转录转位。
Long interspersed element-1 (L1) retrotransposons compose similar to 20% of the mammalian genome, and ongoing L1 retrotransposition events can impact genetic diversity by various mechanisms. Previous studies have demonstrated that endogenous L1 retrotransposition can occur in the germ line and during early embryonic development. In addition, recent data indicate that engineered human L1s can undergo somatic retrotransposition in human neural progenitor cells and that an increase in human-specific L1 DNA content can be detected in the brains of normal controls, as well as in Rett syndrome patients. Here, we demonstrate an increase in the retrotransposition efficiency of engineered human L1s in cells that lack or contain severely reduced levels of ataxia telangiectasia mutated, a serine/threonine kinase involved in DNA damage signaling and neurodegenerative disease. We demonstrate that the increase in L1 retrotransposition in ataxia telangiectasia mutated-deficient cells most likely occurs by conventional target-site primed reverse transcription and generate either longer, or perhaps more, L1 retrotransposition events per cell. Finally, we provide evidence suggesting an increase in human-specific L1 DNA copy number in postmortem brain tissue derived from ataxia telangiectasia patients compared with healthy controls. Together, these data suggest that cellular proteins involved in the DNA damage response may modulate L1 retrotransposition.