Gasior Stephen L, Roy-Engel Astrid M, Deininger Prescott L
Tulane Cancer Center and Department of Epidemiology, SL66, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
DNA Repair (Amst). 2008 Jun 1;7(6):983-9. doi: 10.1016/j.dnarep.2008.02.006. Epub 2008 Apr 18.
Retrotransposons are currently active in the human and mouse genomes contributing to novel disease mutations and genomic variation via de novo insertions. However, little is known about the interactions of non-long terminal repeat (non-LTR) retrotransposons with the host DNA repair machinery. Based on the model of retrotransposition for the human and mouse LINE-1 element, one likely intermediate is an extension of cDNA that is heterologous to the genomic target, a flap intermediate. To determine whether a human flap endonuclease could recognize and process this potential intermediate, the genetic requirement for the ERCC1/XPF heterodimer during LINE-1 retrotransposition was characterized. Reduction of XPF in human cells increased retrotransposition whereas complementation of ERCC1-deficiency in hamster cells reduced retrotransposition. These results demonstrate for the first time that DNA repair enzymes act to limit non-LTR retrotransposition and may provide insight into the genetic instability phenotypes of ercc1 and xpf individuals.
逆转录转座子目前在人类和小鼠基因组中具有活性，通过从头插入导致新的疾病突变和基因组变异。然而，关于非长末端重复（non-LTR）逆转录转座子与宿主DNA修复机制之间的相互作用，我们知之甚少。基于人类和小鼠LINE-1元件的逆转录转座模型，一种可能的中间体是与基因组靶标异源的cDNA延伸，即瓣状中间体。为了确定人类瓣状核酸内切酶是否能够识别并处理这种潜在的中间体，我们对LINE-1逆转录转座过程中ERCC1/XPF异二聚体的遗传需求进行了表征。人类细胞中XPF的减少增加了逆转录转座，而仓鼠细胞中ERCC1缺陷的互补则减少了逆转录转座。这些结果首次证明DNA修复酶的作用是限制非LTR逆转录转座，并可能为深入了解ercc1和xpf个体的遗传不稳定表型提供线索。
