Richardson Sandra R, Narvaiza Iñigo, Planegger Randy A, Weitzman Matthew D, Moran John V
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, United States
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, United States.
Elife. 2014 Apr 24;3:e02008. doi: 10.7554/eLife.02008.
Long INterspersed Element-1 (LINE-1 or L1) retrotransposition poses a mutagenic threat to human genomes. Human cells have therefore evolved strategies to regulate L1 retrotransposition. The APOBEC3 (A3) gene family consists of seven enzymes that catalyze deamination of cytidine nucleotides to uridine nucleotides (C-to-U) in single-strand DNA substrates. Among these enzymes, APOBEC3A (A3A) is the most potent inhibitor of L1 retrotransposition in cultured cell assays. However, previous characterization of L1 retrotransposition events generated in the presence of A3A did not yield evidence of deamination. Thus, the molecular mechanism by which A3A inhibits L1 retrotransposition has remained enigmatic. Here, we have used in vitro and in vivo assays to demonstrate that A3A can inhibit L1 retrotransposition by deaminating transiently exposed single-strand DNA that arises during the process of L1 integration. These data provide a mechanistic explanation of how the A3A cytidine deaminase protein can inhibit L1 retrotransposition.DOI: http://dx.doi.org/10.7554/eLife.02008.001.
长散在核元件1（LINE-1或L1）逆转录转座对人类基因组构成诱变威胁。因此，人类细胞进化出了调控L1逆转录转座的策略。载脂蛋白B mRNA编辑酶催化多肽样3（APOBEC3，A3）基因家族由七种酶组成，这些酶催化单链DNA底物中的胞嘧啶核苷酸脱氨生成尿嘧啶核苷酸（C到U）。在这些酶中，APOBEC3A（A3A）是培养细胞实验中L1逆转录转座最有效的抑制剂。然而，先前对在A3A存在下产生的L1逆转录转座事件的表征并未产生脱氨的证据。因此，A3A抑制L1逆转录转座的分子机制仍然是个谜。在这里，我们使用体外和体内实验来证明，A3A可以通过使L1整合过程中短暂暴露的单链DNA脱氨来抑制L1逆转录转座。这些数据为A3A胞嘧啶脱氨酶蛋白如何抑制L1逆转录转座提供了一个机制解释。DOI: http://dx.doi.org/10.7554/eLife.02008.001
