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首页> 外文期刊>Nature >Nuclear ARP2/3 drives DNA break clustering for homology-directed repair
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Nuclear ARP2/3 drives DNA break clustering for homology-directed repair

机译：核ARP2 / 3推动DNA断裂簇的同源性导向修复

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摘要

DNA double-strand breaks repaired by non-homologous end joining display limited DNA end-processing and chromosomal mobility. By contrast, double-strand breaks undergoing homology-directed repair exhibit extensive processing and enhanced motion. The molecular basis of this movement is unknown. Here, using Xenopus laevis cell-free extracts and mammalian cells, we establish that nuclear actin, WASP, and the actin-nucleating ARP2/3 complex are recruited to damaged chromatin undergoing homology-directed repair. We demonstrate that nuclear actin polymerization is required for the migration of a subset of double-strand breaks into discrete sub-nuclear clusters. Actin-driven movements specifically affect double-strand breaks repaired by homology-directed repair in G2 cell cycle phase; inhibition of actin nucleation impairs DNA end-processing and homology-directed repair. By contrast, ARP2/3 is not enriched at double-strand breaks repaired by non-homologous end joining and does not regulate non-homologous end joining. Our findings establish that nuclear actin-based mobility shapes chromatin organization by generating repair domains that are essential for homology-directed repair in eukaryotic cells.
机译：通过非同源末端连接修复的DNA双链断裂显示出有限的DNA末端加工和染色体移动性。相比之下，经历同源性定向修复的双链断裂表现出广泛的加工和增强的运动。这种运动的分子基础是未知的。在这里，使用非洲爪蟾无细胞提取物和哺乳动物细胞，我们建立了核肌动蛋白，WASP和肌动蛋白成核的ARP2 / 3复合物被募集到受损的染色质，进行同源性定向修复。我们证明核肌动蛋白聚合反应是将双链断裂子集迁移到离散的亚核簇中所必需的。肌动蛋白驱动的运动特别影响在G2细胞周期阶段通过同源性定向修复修复的双链断裂。抑制肌动蛋白成核会损害DNA的最终加工和同源性指导的修复。相比之下，ARP2 / 3不会在通过非同源末端连接修复的双链断裂处富集，并且不会调节非同源末端连接。我们的发现建立了基于核肌动蛋白的迁移性，通过产生对于真核细胞中同源性定向修复必不可少的修复域，可以影响染色质的组织。

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  • 来源
    《Nature》 |2018年第7712期|61-66|共6页
  • 作者

    Schrank Benjamin R.; Aparicio Tomas; Li Yinyin; Chang Wakam; Chait Brian T.; Gundersen Gregg G.; Gottesman Max E.; Gautier Jean;

  • 作者单位

    Columbia Univ, Coll Phys & Surg, Inst Canc Genet, New York, NY 10027 USA;

    Columbia Univ, Coll Phys & Surg, Inst Canc Genet, New York, NY 10027 USA;

    Rockefeller Univ, Lab Mass Spectrometry & Gaseous Ion Chem, 1230 York Ave, New York, NY 10021 USA;

    Columbia Univ, Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY USA;

    Rockefeller Univ, Lab Mass Spectrometry & Gaseous Ion Chem, 1230 York Ave, New York, NY 10021 USA;

    Rockefeller Univ, Lab Mass Spectrometry & Gaseous Ion Chem, 1230 York Ave, New York, NY 10021 USA;

    Columbia Univ, Coll Phys & Surg, Dept Biochem & Biophys, New York, NY USA;

    Columbia Univ, Coll Phys & Surg, Inst Canc Genet, New York, NY 10027 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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