GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government. PTS Granada, Av. de la Ilustración, 114, 18016, Granada, Spain.
Dept. Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Campus Universitario de Cartuja, 18071, Granada, Spain.
Nat Commun. 2020 Nov 11;11(1):5712. doi: 10.1038/s41467-020-19430-4.
Nearly half of the human genome is made of transposable elements (TEs) whose activity continues to impact its structure and function. Among them, Long INterspersed Element class 1 (LINE-1 or L1) elements are the only autonomously active TEs in humans. L1s are expressed and mobilized in different cancers, generating mutagenic insertions that could affect tumor malignancy. Tumor suppressor microRNAs are ∼22nt RNAs that post-transcriptionally regulate oncogene expression and are frequently downregulated in cancer. Here we explore whether they also influence L1 mobilization. We show that downregulation of let-7 correlates with accumulation of L1 insertions in human lung cancer. Furthermore, we demonstrate that let-7 binds to the L1 mRNA and impairs the translation of the second L1-encoded protein, ORF2p, reducing its mobilization. Overall, our data reveals that let-7, one of the most relevant microRNAs, maintains somatic genome integrity by restricting L1 retrotransposition.
人类基因组的近一半由转座元件（TEs）组成，其活性持续影响其结构和功能。其中，长散布元件 1 类（LINE-1 或 L1）元件是人类中唯一自主活跃的 TEs。L1 在不同的癌症中表达和迁移，产生可能影响肿瘤恶性程度的突变插入。肿瘤抑制 microRNAs 是约 22nt 的 RNA，可在后转录水平调节癌基因表达，并且在癌症中经常下调。在这里，我们探讨它们是否也影响 L1 的迁移。我们发现 let-7 的下调与人类肺癌中 L1 插入的积累相关。此外，我们证明 let-7 与 L1 mRNA 结合并损害第二 L1 编码蛋白 ORF2p 的翻译，从而减少其迁移。总体而言，我们的数据表明，let-7 是最相关的 microRNAs 之一，通过限制 L1 反转录来维持体细胞基因组的完整性。
