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Structural basis of long-range to short-range synaptic transition in NHEJ

机译：NHEJ在短程突触过渡的长距离的结构基础

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摘要

DNA double-strand breaks (DSBs) are a highly cytotoxic form of DNA damage and the incorrect repair of DSBs is linked to carcinogenesis~(1,2). The conserved error-prone non-homologous end joining (NHEJ) pathway has a key role in determining the effects of DSB-inducing agents that are used to treat cancer as well as the generation of the diversity in antibodies and T cell receptors~(2,3). Here we applied single-particle cryo-electron microscopy to visualize two key DNA-protein complexes that are formed by human NHEJ factors. The Ku70/80 heterodimer (Ku), the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), DNA ligase IV (LigIV), XRCC4 and XLF form a long-range synaptic complex, in which the DNA ends are held approximately 115 Å apart. Two DNA end-bound subcomplexes comprising Ku and DNA-PKcs are linked by interactions between the DNA-PKcs subunits and a scaffold comprising LigIV, XRCC4, XLF, XRCC4 and LigIV. The relative orientation of the DNA-PKcs molecules suggests a mechanism for autophosphorylation in trans, which leads to the dissociation of DNA-PKcs and the transition into the short-range synaptic complex. Within this complex, the Ku-bound DNA ends are aligned for processing and ligation by the XLF-anchored scaffold, and a single catalytic domain of LigIV is stably associated with a nick between the two Ku molecules, which suggests that the joining of both strands of a DSB involves both LigIV molecules.
机译：DNA双链断裂（DSB）是一种高度细胞毒性的DNA损伤形式，DSB的不正确修复与致癌产生〜（1,2）。保守的误差易于非同源终端连接（NHEJ）途径在确定用于治疗癌症的DSB诱导剂的影响以及抗体和T细胞受体中的多样性的产生〜（2 3）。在这里，我们应用单粒子冷冻电子显微镜，以显示由人NHEJ因子形成的两个关键DNA蛋白复合物。 Ku70 / 80异二聚体（Ku），DNA依赖性蛋白激酶（DNA-PKCS），DNA连接酶IV（LIGIV），XRCC4和XLF的催化亚基形成了长距重突触复合物，其中保持DNA末端大约115Å分开。包含Ku和DNA-PKCs的两种DNA结束的子拷贝用通过DNA-PKCS亚基和包含LIGIV，XRCC4，XLF，XRCC4和LIGIV的支架之间的相互作用连接。 DNA-PKCS分子的相对取向表明跨越式自磷酸化机制，这导致DNA-PKCS的解离和过渡到短程突触复合物中。在该综合体中，Ku-结合的DNA末端与XLF锚定支架的加工和连接进行对准，并且单一的催化结构域与两个KU分子之间的缺口稳定地相关，这表明两条链的连接DSB的涉及既有单杆分子。

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  • 来源
    《Nature》 |2021年第7858期|294-298|共5页
  • 作者

    Siyu Chen; Linda Lee; Tasmin Naila; Susan Fishbain; Annie Wang; Alan E Tomkinson; Susan P Lees-Miller; Yuan He;

  • 作者单位

    Department of Molecular Biosciences Northwestern University|Interdisciplinary Biological Sciences Program Northwestern University;

    Department of Biochemistry and Molecular Biology University of Calgary|Robson DNA Science Centre Charbonneau Cancer Institute University of Calgary;

    Department of Internal Medicine University of New Mexico|Department of Molecular Genetics & Microbiology University of New Mexico|University of New Mexico Comprehensive Cancer Center University of New Mexico;

    Department of Molecular Biosciences Northwestern University;

    Department of Molecular Biosciences Northwestern University;

    Department of Internal Medicine University of New Mexico|Department of Molecular Genetics & Microbiology University of New Mexico|University of New Mexico Comprehensive Cancer Center University of New Mexico;

    Department of Biochemistry and Molecular Biology University of Calgary|Robson DNA Science Centre Charbonneau Cancer Institute University of Calgary;

    Department of Molecular Biosciences Northwestern University|Interdisciplinary Biological Sciences Program Northwestern University|Chemistry of Life Processes Institute Northwestern University|Robert H. Lurie Comprehensive Cancer Center of Northwestern University Northwestern University;

  • 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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