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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Site-specific integration of adeno-associated virus involves partial duplication of the target locus
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Site-specific integration of adeno-associated virus involves partial duplication of the target locus

机译：腺相关病毒的位点特异性整合涉及目标基因座的部分复制

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摘要

A variety of viruses establish latency by integrating their genome into the host genome. The integration event generally occurs in a nonspecific manner, precluding the prediction of functional consequences from resulting disruptions of affected host genes. The nonpathogenic adeno-associated virus (AAV) is unique in its ability to stably integrate in a site-specific manner into the human MBS85 gene. To gain a better understanding of the integration mechanism and the consequences of MBS85 disruption, we analyzed the molecular structure of AAV integrants in various latently infected human cell lines. Our study led to the observation that AAV integration causes an extensive but partial duplication of the target gene. Intriguingly, the molecular organization of the integrant leaves the possibility that a functional copy of the disrupted target gene could potentially be preserved despite the resulting rearrangements. A latently infected, Mbs85-targeted mouse ES cell line was generated to study the functional consequences of the observed duplication-based integration mechanism. AAV-modified ES cell lines continued to self-renew, maintained their multilineage differentiation potential and contributed successfully to mouse development when injected into blastocysts. Thus, our study reveals a viral strategy for targeted genome addition with the apparent absence of functional consequences.
机译：多种病毒通过将其基因组整合到宿主基因组中来建立潜伏期。整合事件通常以非特异性方式发生，从而排除了对受影响宿主基因的破坏导致的功能后果的预测。非病原性腺相关病毒（AAV）以其以位点特异性的方式稳定整合到人MBS85基因中的能力是独特的。为了更好地了解整合机制和MBS85破坏的后果，我们分析了各种潜伏感染人类细胞系中AAV整合剂的分子结构。我们的研究导致观察到，AAV整合引起靶基因的广泛但部分重复。有趣的是，尽管产生了重排，但整合子的分子组织仍保留了可能保留被破坏的靶基因功能性拷贝的可能性。产生了潜伏感染的，靶向Mbs85的小鼠ES细胞系，以研究观察到的基于复制的整合机制的功能后果。 AAV修饰的ES细胞系继续自我更新，保持了其多系分化潜能，并在注入胚泡后成功地促进了小鼠的发育。因此，我们的研究揭示了靶向基因组添加的病毒策略，显然没有功能性后果。

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  • 作者

    Els Henckaerts; Nathalie Dutheil; Nadja Zeltner; Steven Kattman; Erik Kohlbrenner; Peter Ward; Nathalie Clement; Patricia Rebollo; Marion Kennedy; Gordon M. Keller; R. Michael Linden;

  • 作者单位

    Department of Infectious Diseases, King's College London School of Medicine, London SE1 9RT, United Kingdom;

    Department of Infectious Diseases, King's College London School of Medicine, London SE1 9RT, United Kingdom;

    Departments of Gene and Cell Medicine, One Gustave L. Levy Place, New York, NY 10029;

    McEwen Centre for Regenerative Medicine, University Health Network, Toronto, ON, Canada M5G 1L7;

    Departments of Gene and Cell Medicine, One Gustave L. Levy Place, New York, NY 10029;

    Departments of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029;

    Departments of Gene and Cell Medicine, One Gustave L. Levy Place, New York, NY 10029;

    Departments of Gene and Cell Medicine, One Gustave L. Levy Place, New York, NY 10029;

    McEwen Centre for Regenerative Medicine, University Health Network, Toronto, ON, Canada M5G 1L7;

    McEwen Centre for Regenerative Medicine, University Health Network, Toronto, ON, Canada M5G 1L7;

    Department of Infectious Diseases, King's College London School of Medicine, London SE1 9RT, United Kingdom Departments of Gene and Cell Medicine, One Gustave L. Levy Place, New York, NY 10029;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    embryonic stem cells; MBS85; gene targeting; rep; AAVS1;

    机译：胚胎干细胞;MBS85;基因靶向代表AAVS1;

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