Guardian of the Human Genome: Host Defense Mechanisms against LINE-1 Retrotransposition.
Guardian of the Human Genome: Host Defense Mechanisms against LINE-1 Retrotransposition.
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DOI：
10.3389/fchem.2016.00028
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发表时间：
2016
影响因子：
5.5
通讯作者：
Ariumi Y
中科院分区：
文献类型：
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作者：
Ariumi Y
长散布元件1型（LINE-1，L1）是一种移动的遗传元件，约占人类基因组的17%，编码L1反转录转座所需的功能未知的ORF 0、具有RNA结合活性的ORF 1 p和具有核酸内切酶和逆转录酶活性的ORF 2 p。L1利用核酸内切酶（EN）将L1 cDNA插入靶DNA中，从而诱导DNA双链断裂（DSB）。共济失调-毛细血管扩张突变（ATM）被DSB激活，随后ATM信号通路在调节L1反转录转座中起作用。此外，宿主DNA修复机制如非同源末端连接（NHEJ）修复途径也参与了L1反转录转座。另一方面，L1是一种插入诱变剂，它有助于遗传变化，基因组不稳定性和肿瘤发生。事实上，基于高通量测序的方法在多种癌症中鉴定了许多肿瘤特异性体细胞L1插入，例如结肠癌、乳腺癌和肝细胞癌（HCC）。事实上，L1反转录转位似乎是降低HCC肿瘤抑制特性的潜在因素。此外，最近的研究表明，一个特定的病毒-人嵌合转录，HBx-L1，有助于B型肝炎病毒（HBV）相关的肝癌。相反，宿主细胞已经进化出几种防御机制，保护细胞免受逆转录转座，包括通过DNA甲基化和宿主防御因子（如APOBEC 3，MOV 10和SAMHD 1）进行的表观遗传调控，这些防御因子限制了L1作为人类基因组监护人的移动性。在这篇综述中，我专注于体细胞L1插入到人类基因组中的癌症和宿主防御机制对有害的L1插入。
Long interspersed element type 1 (LINE-1, L1) is a mobile genetic element comprising about 17% of the human genome, encoding a newly identified ORF0 with unknown function, ORF1p with RNA-binding activity and ORF2p with endonuclease and reverse transcriptase activities required for L1 retrotransposition. L1 utilizes an endonuclease (EN) to insert L1 cDNA into target DNA, which induces DNA double-strand breaks (DSBs). The ataxia-telangiectasia mutated (ATM) is activated by DSBs and subsequently the ATM-signaling pathway plays a role in regulating L1 retrotransposition. In addition, the host DNA repair machinery such as non-homologous end-joining (NHEJ) repair pathway is also involved in L1 retrotransposition. On the other hand, L1 is an insertional mutagenic agent, which contributes to genetic change, genomic instability, and tumorigenesis. Indeed, high-throughput sequencing-based approaches identified numerous tumor-specific somatic L1 insertions in variety of cancers, such as colon cancer, breast cancer, and hepatocellular carcinoma (HCC). In fact, L1 retrotransposition seems to be a potential factor to reduce the tumor suppressive property in HCC. Furthermore, recent study demonstrated that a specific viral-human chimeric transcript, HBx-L1, contributes to hepatitis B virus (HBV)-associated HCC. In contrast, host cells have evolved several defense mechanisms protecting cells against retrotransposition including epigenetic regulation through DNA methylation and host defense factors, such as APOBEC3, MOV10, and SAMHD1, which restrict L1 mobility as a guardian of the human genome. In this review, I focus on somatic L1 insertions into the human genome in cancers and host defense mechanisms against deleterious L1 insertions.