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Sliding sleeves of XRCC4-XLF bridge DNA and connect fragments of broken DNA

机译：XRCC4-XLF的滑套桥接DNA并连接断裂的DNA片段

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摘要

Non-homologous end joining (NHEJ) is the primary pathway for repairing DNA double-strand breaks (DSBs) in mammalian cells(1). Such breaks are formed, for example, during gene-segment rearrangements in the adaptive immune system or by cancer therapeutic agents. Although the core components of the NHEJ machinery are known, it has remained difficult to assess the specific roles of these components and the dynamics of bringing and holding the fragments of broken DNA together. The structurally similar XRCC4 and XLF proteins are proposed to assemble as highly dynamic filaments at (or near) DSBs(2). Here we show, using dual-and quadruple-trap optical tweezers combined with fluorescence microscopy, how human XRCC4, XLF and XRCC4-XLF complexes interact with DNA in real time. We find that XLF stimulates the binding of XRCC4 to DNA, forming heteromeric complexes that diffuse swiftly along the DNA. Moreover, we find that XRCC4-XLF complexes robustly bridge two independent DNA molecules and that these bridges are able to slide along the DNA. These observations suggest that XRCC4-XLF complexes form mobile sleeve-like structures around DNA that can reconnect the broken ends very rapidly and hold them together. Understanding the dynamics and regulation of this mechanism will lead to clarification of how NHEJ proteins are involved in generating chromosomal translocations(3,4).
机译：非同源末端连接（NHEJ）是修复哺乳动物细胞中DNA双链断裂（DSB）的主要途径（1）。这样的断裂例如在适应性免疫系统中的基因片段重排过程中或由癌症治疗剂形成。尽管NHEJ机制的核心组件是已知的，但仍然很难评估这些组件的特定作用以及将破碎的DNA片段聚集在一起并保持在一起的动力学。结构相似的XRCC4和XLF蛋白被提议在DSBs处（或附近）组装成高动态细丝（2）。在这里，我们展示了使用双阱和四阱光镊与荧光显微镜相结合，人类XRCC4，XLF和XRCC4-XLF复合物如何与DNA实时相互作用。我们发现XLF刺激XRCC4与DNA的结合，形成沿DNA迅速扩散的异聚复合物。此外，我们发现XRCC4-XLF复合物牢固地桥接了两个独立的DNA分子，并且这些桥能够沿着DNA滑动。这些观察结果表明，XRCC4-XLF复合物在DNA周围形成了可移动的套筒状结构，可以非常快速地重新连接断裂的末端并将其固定在一起。了解这种机制的动力学和调控机制将有助于弄清NHEJ蛋白如何参与染色体易位（3,4）。

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  • 来源
    《Nature》 |2016年第7613期|566-569|共4页
  • 作者

    Brouwer Ineke; Sitters Gerrit; Candelli Andrea; Heerema Stephanie J.; Heller Iddo; de Melo Abinadabe J.; Zhang Hongshan; Normanno Davide; Modesti Mauro; Peterman Erwin J. G.; Wuite Gijs J. L.;

  • 作者单位

    Vrije Univ Amsterdam, Dept Phys & Astron, NL-1081 HV Amsterdam, Netherlands|Vrije Univ Amsterdam, LaserLab, NL-1081 HV Amsterdam, Netherlands;

    Vrije Univ Amsterdam, Dept Phys & Astron, NL-1081 HV Amsterdam, Netherlands|Vrije Univ Amsterdam, LaserLab, NL-1081 HV Amsterdam, Netherlands|LUMICKS BV, NL-1081 HV Amsterdam, Netherlands;

    Vrije Univ Amsterdam, Dept Phys & Astron, NL-1081 HV Amsterdam, Netherlands|Vrije Univ Amsterdam, LaserLab, NL-1081 HV Amsterdam, Netherlands|LUMICKS BV, NL-1081 HV Amsterdam, Netherlands;

    Vrije Univ Amsterdam, Dept Phys & Astron, NL-1081 HV Amsterdam, Netherlands|Vrije Univ Amsterdam, LaserLab, NL-1081 HV Amsterdam, Netherlands|Delft Univ Technol, Kavli Inst Nanosci, NL-2628 CJ Delft, Netherlands;

    Vrije Univ Amsterdam, Dept Phys & Astron, NL-1081 HV Amsterdam, Netherlands|Vrije Univ Amsterdam, LaserLab, NL-1081 HV Amsterdam, Netherlands;

    Aix Marseille Univ, Canc Res Ctr Marseille, Inst Paoli Calmettes, CNRS,UMR7258,Inserm,U1068,UM105, F-13273 Marseilles, France;

    Aix Marseille Univ, Canc Res Ctr Marseille, Inst Paoli Calmettes, CNRS,UMR7258,Inserm,U1068,UM105, F-13273 Marseilles, France;

    Aix Marseille Univ, Canc Res Ctr Marseille, Inst Paoli Calmettes, CNRS,UMR7258,Inserm,U1068,UM105, F-13273 Marseilles, France;

    Aix Marseille Univ, Canc Res Ctr Marseille, Inst Paoli Calmettes, CNRS,UMR7258,Inserm,U1068,UM105, F-13273 Marseilles, France;

    Vrije Univ Amsterdam, Dept Phys & Astron, NL-1081 HV Amsterdam, Netherlands|Vrije Univ Amsterdam, LaserLab, NL-1081 HV Amsterdam, Netherlands;

    Vrije Univ Amsterdam, Dept Phys & Astron, NL-1081 HV Amsterdam, Netherlands|Vrije Univ Amsterdam, LaserLab, NL-1081 HV Amsterdam, Netherlands;

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