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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The BRC repeats of human BRCA2 differentially regulate RAD51 binding on single- versus double-stranded DNA to stimulate strand exchange
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The BRC repeats of human BRCA2 differentially regulate RAD51 binding on single- versus double-stranded DNA to stimulate strand exchange

机译：人类BRCA2的BRC重复序列差异调节RAD51在单链与双链DNA上的结合以刺激链交换

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摘要

The breast and ovarian cancer suppressor BRCA2 controls the enzyme RAD51 during homologous DNA recombination (HDR) to preserve genome stability. BRCA2 binds to RAD51 through 8 conserved BRC repeat motifs dispersed in an 1127-residue region (BRCA2_([BRC1-8])). Here, we show that BRCA2_([BRC1-8])] exerts opposing effects on the binding of RAD51 to single stranded (ss) versus double-stranded (ds) DNA substrates, enhancing strand exchange. BRCA2_([BRC1-8]) alters the electrophoretic mobility of RAD51 bound to an ssDNA substrate, accompanied by an increase in ssDNA-bound protein assemblies, revealed by electron microscopy. Single-molecule fluorescence spec-troscopy shows that BRCA2_([BRC1-8]) promotes RAD51 loading onto ssDNA. In contrast, BRCA2_([BRC1-8]) has a different effect on RAD51 assembly on dsDNA; it suppresses and slows this process. When homologous ssDNA and dsDNA are both present, BRCA2[brci-8] stimulates strand exchange, with delayed RAD51 loading onto dsDNA accompanying the appearance of joint molecules representing recombination products. Collectively, our findings suggest that BRCA2_([BRC1-8]) targets RAD51 to ssDNA while inhibiting dsDNA binding and that these contrasting activities together bolster one another to stimulate HDR. Our work provides fresh insight into the mechanism of HDR in humans, and its regulation by the BRCA2 tumor suppressor.
机译：乳腺癌和卵巢癌抑制物BRCA2在同源DNA重组（HDR）期间控制酶RAD51，以保持基因组稳定性。 BRCA2通过分布在1127个残基区域（BRCA2 _（[[BRC1-8]））的8个保守BRC重复基序与RAD51结合。在这里，我们显示BRCA2 _（[[BRC1-8]）]对RAD51与单链（ss）与双链（ds）DNA底物的结合施加相反的作用，从而增强了链交换。 BRCA2 _（[BRC1-8]）改变结合到ssDNA底物上的RAD51的电泳迁移率，并伴随着通过电子显微镜显示的ssDNA结合蛋白装配的增加。单分子荧光光谱表明，BRCA2 _（[[BRC1-8]）促进RAD51加载到ssDNA上。相反，BRCA2 _（[BRC1-8]）对RAD51在dsDNA上的组装有不同的影响。它抑制并减慢了此过程。当同源的ssDNA和dsDNA都存在时，BRCA2 [brci-8]刺激链交换，同时RAD51加载到dsDNA上的时间延迟，伴随着代表重组产物的联合分子的出现。总的来说，我们的发现表明BRCA2 _（[[BRC1-8]）在抑制dsDNA结合的同时将RAD51靶向ssDNA，并且这些相反的活性相互促进以刺激HDR。我们的工作为人类HDR的机制及其由BRCA2肿瘤抑制剂的调控提供了新的见解。

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    Mahmud K. K. Shivji; Shreyas R. Mukund; Eeson Rajendra; Shaoxia Chen; Judith M. Short; Jane Savill; David Klenerman; Ashok R. Venkitaraman;

  • 作者单位

    The Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ,United Kingdom;

    The Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ,United Kingdom Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom;

    The Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ,United Kingdom;

    The Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, United Kingdom;

    The Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, United Kingdom;

    The Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ,United Kingdom;

    Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom;

    The Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ,United Kingdom;

  • 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
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  • 关键词

    DNA recombination; electron microscopy; single-molecule fluorescence spectroscopy; tumor suppressor;

    机译：DNA重组;电子显微镜;单分子荧光光谱法;抑癌剂;

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