Human LINE-1 retrotransposon induces DNA damage and apoptosis in cancer cells.
Human LINE-1 retrotransposon induces DNA damage and apoptosis in cancer cells.
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DOI：
10.1186/1475-2867-6-13
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发表时间：
2006-05-02
影响因子：
5.8
通讯作者：
Haoudi A
中科院分区：
文献类型：
--
作者：
Belgnaoui SM;Gosden RG;Semmes OJ;Haoudi A
长散布核元件 (LINE)、Alu 和内源性逆转录病毒 (ERV) 约占人类 DNA 的 45%。 LINE-1 也称为 L1，是人类基因组中最常见的非 LTR 反转录转座子家族，约占基因组的 17%。 L1 元件需要使用 L1 编码的核酸内切酶整合到染色体目标位点，这会产生惊人的 DNA 断裂，从而使新转置的 L1 拷贝能够整合到基因组中。癌细胞中的 L1 表达和逆转录转座可能会导致转录失调、插入突变、DNA 断裂和重组频率增加，从而导致基因组不稳定。然而，关于 L1 诱导的遗传不稳定性的机制及其对癌细胞生长和增殖的影响的证据很少。我们报告说，L1 具有基因组不稳定效应，表现为 γ-H2AX 焦点的积累，这是对 DNA 链断裂的早期反应，与通过 G2/M 积累的异常细胞周期进程和诱导乳腺癌细胞凋亡有关。此外，我们发现，佐剂 L1 激活与辐射结合时可能会导致超加成杀伤，通过诱导细胞凋亡（我们通过 Bax 激活检测到）来增强辐射致死率。 L1 逆转录转座通过 L1 编码的核酸内切酶产生 DNA 断裂而被视为 DNA 损伤事件。 L1 激活和辐射之间明显的协同相互作用可以进一步用于靶向诱导癌细胞死亡。因此，反转录转座子，特别是 L1，在 DNA 损伤和修复中的作用对于理解致突变性以及潜在地控制细胞增殖和凋亡具有更大的意义。
Long interspersed nuclear elements (LINEs), Alu and endogenous retroviruses (ERVs) make up some 45% of human DNA. LINE-1 also called L1, is the most common family of non-LTR retrotransposons in the human genome and comprises about 17% of the genome. L1 elements require the integration into chromosomal target sites using L1-encoded endonuclease which creates staggering DNA breaks allowing the newly transposed L1 copies to integrate into the genome. L1 expression and retrotransposition in cancer cells might cause transcriptional deregulation, insertional mutations, DNA breaks, and an increased frequency of recombinations, contributing to genome instability. There is however little evidence on the mechanism of L1-induced genetic instability and its impact on cancer cell growth and proliferation. We report that L1 has genome-destabilizing effects indicated by an accumulation of γ-H2AX foci, an early response to DNA strand breaks, in association with an abnormal cell cycle progression through a G2/M accumulation and an induction of apoptosis in breast cancer cells. In addition, we found that adjuvant L1 activation may lead to supra-additive killing when combined with radiation by enhancing the radiation lethality through induction of apoptosis that we have detected through Bax activation. L1 retrotransposition is sensed as a DNA damaging event through the creation DNA breaks involving L1-encoded endonuclease. The apparent synergistic interaction between L1 activation and radiation can further be utilized for targeted induction of cancer cell death. Thus, the role of retrotransoposons in general, and of L1 in particular, in DNA damage and repair assumes larger significance both for the understanding of mutagenicity and, potentially, for the control of cell proliferation and apoptosis.
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影响因子：
14.9
作者：
Farkash EA;Kao GD;Horman SR;Prak ET
通讯作者：
Prak ET
影响因子：
3.5
作者：
Goodier, JL;Ostertag, EM;Kazazian, HH
通讯作者：
Kazazian, HH
影响因子：
11.4
作者：
Hohjoh, H;Singer, MF
通讯作者：
Singer, MF
影响因子：
64.5
作者：
Gilbert, N;Lutz-Prigge, S;Moran, JV
通讯作者：
Moran, JV
影响因子：
--
作者：
Haoudi, A;Semmes, OJ;Cannon, RE
通讯作者：
Cannon, RE