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The RAG2 C terminus suppresses genomic instability and lymphomagenesis

机译：RAG2 C末端抑制基因组不稳定和淋巴瘤的发生

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摘要

Misrepair of DNA double-strand breaks produced by the V(D)J recombinase (the RAG1/RAG2 proteins) at immunoglobulin (Ig) and T cell receptor (Tcr) loci has been implicated in pathogenesis of lymphoid malignancies in humans and in mice. Defects in DNA damage response factors such as ataxia telangiectasia mutated (ATM) protein and combined deficiencies in classical non-homologous end joining and p53 predispose to RAG-initiated genomic rearrangements and lymphomagenesis. Although we showed previously that RAG1/RAG2 shepherd the broken DNA ends to classical non-homologous end joining for proper repair, roles for the RAG proteins in preserving genomic stability remain poorly defined. Here we show that the RAG2 carboxy (C) terminus, although dispensable for recombination, is critical for maintaining genomic stability. Thymocytes from 'cortf Rag2 homozygotes (Rag2~(c/c) mice) show dramatic disruption of TcralS locus integrity. Furthermore, all Rag2~(c/c) p53~(-/-) mice, unlike Rag1~(c/c) p53~(-/-)and p53~(-/-) animals, rapidly develop thymic lymphomas bearing complex chromosomal translocations, amplifications and deletions involving the Tcra/dand Igh loci. We also find these features in lymphomas from Atm~(-/-) mice. We show that, like ATM-deficiency, core RAG2 severely destabilizes the RAG post-cleavage complex. These results reveal a novel genome guardian role for RAG2 and suggest that similar 'end release/ end persistence' mechanisms underlie genomic instability and lymphomagenesis in Rag2~(c/c) p53~(-/-) and Atm~(-/-) mice.%由“V(D)J重组酶”(RAG1/RAG2蛋白)在免疫rn球蛋白(Igh)和T-细胞受体(Tcr)位点上所产生rn的DNAA链断裂的误修复，已被发现与恶性淋rn巴瘤的病变有关。在这篇文章中，作者们发现，rnRAG2 C-terminiJs是保持基因组稳定性的关rn键。与Rag1c／c p53-／-及p53-／-小鼠不同的rn是，Rag2c／c p53-／-小鼠迅速形成含有涉及Tcrrna／8和Igh位点的复杂染色体转位、放大和删rn除的胸腺淋巴瘤。这些结果显示了RAG2作为rn“基因组卫士”的一个新角色，并且说明，类rn似的“end release／end persisterice”机制是造rn成Rag2c／c p53-／-和Atm-／-小鼠基因组不稳定rn及形成淋巴瘤的原因。
机译：V（D）J重组酶（RAG1 / RAG2蛋白）在免疫球蛋白（Ig）和T细胞受体（Tcr）基因座处产生的DNA双链断裂修复不正确，已被证实与人类和小鼠淋巴恶性肿瘤的发病机理有关。 DNA损伤反应因子中的缺陷，例如共济失调毛细血管扩张突变（ATM）蛋白，以及经典非同源末端连接和p53的综合缺陷，容易导致RAG引发的基因组重排和淋巴瘤的发生。尽管我们之前已经证明RAG1 / RAG2将断裂的DNA末端延伸到经典的非同源末端以进行适当的修复，但是RAG蛋白质在保持基因组稳定性方面的作用仍然不清楚。在这里，我们显示了RAG2羧基（C）末端，尽管可重组，但对于维持基因组稳定性至关重要。 'cortf Rag2纯合子（Rag2〜（c / c）小鼠）的胸腺细胞显示TcralS基因座完整性的急剧破坏。此外，与Rag1〜（c / c）p53〜（-/-）和p53〜（-/-）动物不同，所有Rag2〜（c / c）p53〜（-/-）小鼠均迅速发展出携带复合物的胸腺淋巴瘤涉及Tcra / dand Igh基因座的染色体易位，扩增和缺失。我们还在Atm〜（-/-）小鼠的淋巴瘤中发现了这些特征。我们表明，像ATM缺陷一样，核心RAG2严重破坏了RAG裂解后复合物的稳定性。这些结果揭示了RAG2的新型基因组保护作用，并表明相似的“末端释放/末端持久性”机制是Rag2〜（c / c）p53〜（-/-）和Atm〜（-/-）基因组不稳定和淋巴瘤发生的基础。小鼠。％由“ V（D）J重组酶”（RAG1 / RAG2蛋白）在免疫rn球蛋白（Igh）和T细胞受体（Tcr）位点上所产生的DNAA链断裂的错误修复，在这篇文章中，作者们发现，rnRAG2 C-terminiJs是保持基因组稳定性的关rn键。与Rag1c ／ c p53-／-和p53-／-小鼠不同的rn是，Rag2c ／ c p53-／-小鼠迅速形成含有涉及Tcrrna ／ 8和Igh位点的复杂染色体转位，放大和缩小rn除的胸腺淋巴瘤。这些结果显示了RAG2作为rn “基因组卫士”的一个新角色，并且说明，类rn似的“终释放／终持久性”机制是造rn成Rag2c ／ c p53-／-和Atm-／-小鼠基因组异常rn和形成淋巴瘤的原因。

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  • 来源
    《Nature》 |2011年第7336期|p.119-123|共5页
  • 作者

    Ludovic Deriano; Julie Chaumeil; Marc Coussens; Asha Multani; YiFan Chou; Alexander V. Alekseyenko; Sandy Chang; Jane A. Skok; David B. Roth;

  • 作者单位

    Department of Pathology, New York University School of Medicine, New York, NY 10016, USA;

    Department of Pathology, New York University School of Medicine, New York, NY 10016, USA;

    Department of Pathology, New York University School of Medicine, New York, NY 10016, USA;

    Department of Genetics, The M.D, Anderson Cancer Center, Houston, TX 77030, USA;

    Department of Pathology, New York University School of Medicine, New York, NY 10016, USA;

    Department of Medicine, Division of Clinical Pharmacology, Centerfor Health Informaticsand Bioinformatics, New York University School of Medicine, NY 10016, USA;

    Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA;

    Department of Pathology, New York University School of Medicine, New York, NY 10016, USA,Department of Immunology and Molecular Pathology, Division of Infection and Immunity, University College London, London W1T 4JF, UK;

    Department of Pathology, New York University School of Medicine, New York, NY 10016, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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