文章：

癌症中的转座因子

Transposable elements in cancer

原文发布日期：2017-06-09

DOI: 10.1038/nrc.2017.35

类型: Review Article

开放获取: 否

要点：

1. Much of the human genome is repetitive sequence derived from transposable elements. These include copy-and-paste retrotransposons and cut-and-paste DNA transposons. Only retrotransposons are active as undomesticated mobile DNAs in humans.
2. Ongoing retrotransposition in humans is attributed to long interspersed element-1 (LINE-1; also known as L1). Its activity creates genomic structural variants in human populations and alterations in cancer genomes. Endogenous retroviruses persist as promoter and protein-coding sequences.
3. LINE-1 encodes open reading frame 1p (ORF1p) and ORF2p proteins. ORF1p is an RNA binding protein widely expressed in human malignancies. ORF2p encodes endonuclease and reverse transcriptase activities essential for retrotransposition.
4. LINE-1 activity generates new copies of itself, and also other sequences, including Alu and short interspersed element (SINE)–variable number tandem repeat (VNTR)–Alu (SVA) retrotransposons, pseudogene copies of messenger transcripts and U6 ribosomal RNAs (rRNAs).
5. In cancer, source LINE-1 elements escape genomic DNA methylation and transcriptional repression to contribute new LINE-1 insertions. Different source elements may be active over different phases of the evolution of a cancer.
6. Somatically acquired LINE-1 insertions can cause driver mutations, particularly in gastrointestinal tract tumours, which support high levels of retrotransposition. Distinguishing contributing mutations from inert passenger mutations is an important challenge for the field.

要点翻译：

1. 人类基因组的大部分是由转座因子衍生的重复序列组成。这些序列包括复制粘贴型逆转录转座子和剪切粘贴型DNA转座子。在人类中，只有逆转录转座子作为未经驯化的可移动DNA保持活性。
2. 人类体内持续的逆转录转座活动主要归因于长散在核元件1（LINE-1）。其活性在人类群体中创建基因组结构变异，并在癌症基因组中引发改变。内源性逆转录病毒以启动子和蛋白质编码序列的形式持续存在。
3. LINE-1编码开放阅读框1p（ORF1p）和ORF2p蛋白。ORF1p是一种在人类恶性肿瘤中广泛表达的RNA结合蛋白。ORF2p则编码对逆转录转座至关重要的内切核酸酶和逆转录酶活性。
4. LINE-1的活性不仅生成自身的新拷贝，还产生其他序列，包括Alu元件、短散在核元件-可变数目串联重复-Alu（SVA）逆转录转座子、信使RNA的假基因拷贝以及U6核糖体RNA。
5. 在癌症中，源LINE-1元件逃脱基因组DNA甲基化和转录抑制，导致新的LINE-1插入。不同的源元件可能在癌症演化的不同阶段保持活性。
6. 体细胞获得的LINE-1插入可引发驱动突变，尤其在支持高水平逆转录转座的胃肠道肿瘤中。区分功能性突变与惰性过客突变是该领域面临的重要挑战。

英文摘要：

Transposable elements give rise to interspersed repeats, sequences that comprise most of our genomes. These mobile DNAs have been historically underappreciated — both because they have been presumed to be unimportant, and because their high copy number and variability pose unique technical challenges. Neither impediment now seems steadfast. Interest in the human mobilome has never been greater, and methods enabling its study are maturing at a fast pace. This Review describes the activity of transposable elements in human cancers, particularly long interspersed element-1 (LINE-1). LINE-1 sequences are self-propagating, protein-coding retrotransposons, and their activity results in somatically acquired insertions in cancer genomes. Altered expression of transposable elements and animation of genomic LINE-1 sequences appear to be hallmarks of cancer, and can be responsible for driving mutations in tumorigenesis.

摘要翻译： 

转座元件产生了散布重复序列，这些序列构成了我们基因组的大部分。这些可移动的DNA历来被低估——一方面是因为它们被认为不重要，另一方面则因其高拷贝数和变异性带来了独特的技术挑战。如今，这两个障碍似乎都不再不可逾越。对人类“ mobilome”（可移动基因组）的兴趣从未如此高涨，相关研究方法也在迅速成熟。本文综述了转座元件在人类癌症中的活性，特别是长散布元件-1（LINE-1）。LINE-1序列是可自我扩增、编码蛋白质的逆转录转座子，其活性导致癌症基因组中出现体细胞获得性插入。转座元件表达的改变以及基因组LINE-1序列的“激活”似乎是癌症的标志，并可能在肿瘤发生中驱动突变。

原文链接：

Transposable elements in cancer