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Mechanism of the ATP-dependent DNA end-resection machinery from Saccharomyces cerevisiae

机译：酿酒酵母ATP依赖的DNA末端切除机制的机制。

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摘要

If not properly processed and repaired, DNA double-strand breaks (DSBs) can give rise to deleterious chromosome rearrangements, which could ultimately lead to the tumour phenotype. DSB ends are resected in a 5' to 3' fashion in cells, to yield single-stranded DNA (ssDNA) for the recruitment of factors critical for DNA damage checkpoint activation and repair by homologous recombination2. The resection process involves redundant pathways consisting of nudeases, DNA helicases and associated proteins. Being guided by recent genetic studies, we have reconstituted the first eukaryotic ATP-dependent DNA end-resection machinery comprising the Saccharomyces cerevisiae Mre11-Rad50-Xrs2 (MRX) complex, the Sgs1-Top3-Rmil complex, Dna2 protein and the heterotrimeric ssDNA-binding protein RPA. Here we show that DNA strand separation during end resection is mediated by the Sgs1 helicase function, in a manner that is enhanced by Top3-Rmi1 and MRX. In congruence with genetic observations6, although the Dna2 nuclease activity is critical for resection, the Mre11 nuclease activity is dispensable. By examining the top3 Y356F allele and its encoded protein, we provide evidence that the topoisomerase activity of Top3, although critical for the suppression of crossover recombination, is not needed for resection either in cells or in the reconstituted system. Our results also unveil a multifaceted role of RPA, in the sequestration of ssDNA generated by DNA unwinding, enhancement of 5' strand incision, and protection of the 3' strand. Our reconstituted system should serve as a useful model for delineating the mechanistic intricacy of the DNA break resection process in eukaryotes.
机译：如果未正确处理和修复，DNA双链断裂（DSB）可能引起有害的染色体重排，最终可能导致肿瘤表型。将DSB末端以5'至3'的方式在细胞中切除，以产生单链DNA（ssDNA），以募集对DNA损伤检查点激活和通过同源重组修复2至关重要的因子。切除过程涉及由裸酶，DNA解旋酶和相关蛋白组成的冗余途径。在最近的遗传研究的指导下，我们重建了第一个真核生物ATP依赖的DNA末端切除机制，包括酿酒酵母Mre11-Rad50-Xrs2（MRX）复合物，Sgs1-Top3-Rmil复合物，Dna2蛋白和异三聚体ssDNA-结合蛋白RPA。在这里，我们显示末端切除过程中的DNA链分离是由Sgs1解旋酶功能介导的，其方式由Top3-Rmi1和MRX增强。与遗传学观察结果一致[6]，尽管Dna2核酸酶活性对于切除至关重要，但Mre11核酸酶活性却是必不可少的。通过检查top3 Y356F等位基因及其编码的蛋白质，我们提供了证据，尽管Top3的拓扑异构酶活性对于抑制交叉重组至关重要，但在细胞或重组系统中均不需要切除。我们的研究结果还揭示了RPA在隔离由DNA解链产生的ssDNA，增强5'链切口和保护3'链中的多重作用。我们的重组系统应作为描述真核生物中DNA断裂切除过程机械复杂性的有用模型。

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  • 来源
    《Nature》 |2010年第7311期|P.108-111|共4页
  • 作者

    Hengyao Niu; Woo-Hyun Chung; Zhu Zhu; Youngho Kwon; Weixing Zhao; Peter Chi; Rohit Prakash; Changhyun Seong; Dongqing Liu; Lucy Lu; Grzegorz Ira; Patrick Sung;

  • 作者单位

    Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    rnSepartment of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA;

    rnSepartment of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA;

    rnDepartment of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    rnDepartment of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    rnDepartment of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    rnDepartment of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    rnDepartment of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    rnDepartment of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    rnDepartment of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    rnSepartment of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA;

    rnDepartment of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, 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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