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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Quaternary structure of the human Cdt1-Geminin complex regulates DNA replication licensing
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Quaternary structure of the human Cdt1-Geminin complex regulates DNA replication licensing

机译:人类Cdt1-Geminin复合物的四级结构调节DNA复制许可

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摘要

All organisms need to ensure that no DNA segments are rerepli-cated in a single cell cycle. Eukaryotes achieve this through a process called origin licensing, which involves tight spatiotemporal control of the assembly of prereplicative complexes (pre-RCs) onto chromatin. Cdt1 is a key component and crucial regulator of pre-RC assembly. In higher eukaryotes, timely inhibition of Cdt1 by Gemi-nin is essential to prevent DNA rereplication. Here, we address the mechanism of DNA licensing inhibition by Geminin, by combining X-ray crystallography, small-angle X-ray scattering, and functional studies in Xenopus and mammalian cells. Our findings show that the Cdt1:Geminin complex can exist in two distinct forms, a "permissive" heterotrimer and an "inhibitory" heterohexamer. Specific Cdt1 residues, buried in the heterohexamer, are important for licensing. We postulate that the transition between the heterotrimer and the heterohexamer represents a molecular switch between licensing-competent and licensing-defective states.
机译:所有生物都需要确保在单个细胞周期中不复制任何DNA片段。真核生物通过称为起源许可的过程来实现这一目标,该过程涉及对复制前复合物(pre-RCs)组装到染色质上的紧密时空控制。 Cdt1是预RC组装的关键组件和关键调节器。在高等真核生物中,由Gemi-nin适时抑制Cdt1对防止DNA复制至关重要。在这里,我们通过结合X射线晶体学,小角度X射线散射以及非洲爪蟾和哺乳动物细胞的功能研究来解决Geminin抑制DNA许可的机制。我们的发现表明Cdt1:Geminin复合物可以两种不同的形式存在,一种“允许的”异三聚体和一种“抑制性的”异六聚体。埋在异六聚体中的特定Cdt1残基对于许可很重要。我们假设异三聚体和异六聚体之间的过渡代表了在有许可能力的状态和有缺陷许可的状态之间的分子转换。

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  • 作者单位

    Department of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands Division of Molecular Structure, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom;

    Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom;

    Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom;

    Departments of Pharmacology, Medical School, University of Patras, 26500 Rio, Patras, Greece;

    Department of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands;

    Department of Medical Oncology and Cancer Genomics Center, Laboratory of Experimental Oncology, University Medical Center Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands;

    Department of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands;

    Department of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands;

    European Molecular Biology Laboratory, Hamburg Outstation, Notkestrasse 85, D-22603 Hamburg, Germany;

    Departments of Biology, Medical School, University of Patras, 26500 Rio, Patras, Greece Cancer Epigenetics and Biology Program (PEBC), Catalan Institute of Oncology, 08907 L'Hospitalet, Barcelona, Catalonia, Spain;

    Departments of Biology, Medical School, University of Patras, 26500 Rio, Patras, Greece;

    Department of Medical Oncology and Cancer Genomics Center, Laboratory of Experimental Oncology, University Medical Center Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands;

    Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom;

    European Molecular Biology Laboratory, Hamburg Outstation, Notkestrasse 85, D-22603 Hamburg, Germany;

    Departments of Pharmacology, Medical School, University of Patras, 26500 Rio, Patras, Greece;

    Department of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands;

  • 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

    solution structure; X-ray structure; pre-RC; cell cycle;

    机译:解决方案结构;X射线结构;RC前细胞周期;

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