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Purified human BRCA2 stimulates RAD51-mediated recombination

机译：纯化的人BRCA2刺激RAD51介导的重组

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摘要

Mutation of the breast cancer susceptibility gene, BRCA2, leads to breast and ovarian cancers. Mechanistic insight into the functions of human BRCA2 has been limited by the difficulty of isolating this large protein (3,418 amino acids). Here we report the purification of full-length BRCA2 and show that it both binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA). BRCA2 acts by targeting RAD51 to ssDNA over double-stranded DNA, enabling RAD51 to displace replication protein-A (RPA) from ssDNA and stabilizing RAD51-ssDNA filaments by blocking ATP hydrolysis. BRCA2 does not anneal ssDNA complexed with RPA, implying it does not directly function in repair processes that involve ssDNA annealing. Our findings show that BRCA2 is a key mediator of homologous recombination, and they provide a molecular basis for understanding how this DNA repair process is disrupted by BRCA2 mutations, which lead to chromosomal instability and cancer.
机译：乳腺癌易感基因BRCA2的突变会导致乳腺癌和卵巢癌。分离大蛋白（3,418个氨基酸）的困难限制了对人BRCA2功能的机械洞察力。在这里，我们报告全长BRCA2的纯化，并表明它既与RAD51结合，又通过促进RAD51在单链DNA（ssDNA）上的组装来增强重组DNA的修复。 BRCA2的作用是通过将RAD51靶向双链DNA上的ssDNA，使RAD51能够取代ssDNA的复制蛋白A（RPA），并通过阻止ATP水解来稳定RAD51-ssDNA细丝。 BRCA2不会对与RPA复合的ssDNA进行退火，这意味着它在涉及ssDNA退火的修复过程中无法直接发挥作用。我们的发现表明BRCA2是同源重组的关键介体，它们为理解DNA修复过程如何被BRCA2突变破坏而提供了分子基础，BRCA2突变导致染色体不稳定和癌症。

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  • 来源
    《Nature》 |2010年第7316期|P.678-683ⅲ|共7页
  • 作者

    Ryan B. Jensen; Aura Carreira; Stephen C. Kowalczykowski;

  • 作者单位

    Department ot Microbiology, University of California, Davis, California 95616, USA Department of Molecular & Cellular Biology, University of California, Davis, California 95616, USA;

    rnDepartment ot Microbiology, University of California, Davis, California 95616, USA Department of Molecular & Cellular Biology, University of California, Davis, California 95616, USA;

    rnDepartment ot Microbiology, University of California, Davis, California 95616, USA Department of Molecular & Cellular Biology, University of California, Davis, California 95616, 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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