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DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes

机译:DNA损伤定义了B淋巴细胞复发性染色体易位的位点

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摘要

Recurrent chromosomal translocations underlie both haematopoietic and solid tumours. Their origin has been ascribed to selection of random rearrangements, targeted DNA damage, or frequent nuclear interactions between translocation partners; however, the relative contribution of each of these elements has not been measured directly or on a large scale. Here we examine the role of nuclear architecture and frequency of DNA damage in the genesis of chromosomal translocations by measuring these parameters simultaneously in cultured mouse B lymphocytes. In the absence of recurrent DNA damage, translocations between Igh or Myc and all other genes are directly related to their contact frequency. Conversely, translocations associated with recurrent site-directed DNA damage are proportional to the rate of DNA break formation, as measured by replication protein A accumulation at the site of damage. Thus, non-targeted rearrangements reflect nuclear organization whereas DNA break formation governs the location and frequency of recurrent translocations, including those driving B-cell malignancies.
机译:复发性染色体易位是造血和实体瘤的基础。它们的起源归因于随机重排,靶向DNA损伤或易位伴侣之间频繁的核相互作用的选择。但是,这些元素中每个元素的相对贡献尚未直接或大规模地测量。在这里,我们通过在培养的小鼠B淋巴细胞中同时测量这些参数,来检查核结构的作用和DNA损伤频率在染色体易位发生中的作用。在没有复发性DNA损伤的情况下,Igh或Myc与所有其他基因之间的易位与它们的接触频率直接相关。相反,与复发性定点DNA损伤相关的易位与DNA断裂形成的速率成正比,如通过损伤位点处复制蛋白A的积累所测量的。因此,非靶向的重排反应反映了核组织,而DNA断裂的形成控制着反复易位的位置和频率,包括那些驱动B细胞恶性肿瘤的易位。

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  • 来源
    《Nature》 |2012年第7392期|p.69-74|共6页
  • 作者单位

    Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Genomics & Immunity, NIAMS, NCI, National Institutes of Health, Bethesda,Maryland 20892, USA;

    Genomics & Immunity, NIAMS, NCI, National Institutes of Health, Bethesda,Maryland 20892, USA;

    Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA;

    Genomics & Immunity, NIAMS, NCI, National Institutes of Health, Bethesda,Maryland 20892, USA;

    Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA;

    Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA,Medical School of Ribeirao Preto/USP, Departmento of Genetics, 8 National Institute of Science and Technology for Stem Cells and Cell Therapy and Center for Cell-based Therapy, Ribeirao Preto, SP 14051-140, Brazil;

    Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA;

    Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Genomics & Immunity, NIAMS, NCI, National Institutes of Health, Bethesda,Maryland 20892, USA;

    Biodata Mining and Discovery, NIAMS, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Genomics & Immunity, NIAMS, NCI, National Institutes of Health, Bethesda,Maryland 20892, USA;

    Genomics & Immunity, NIAMS, NCI, National Institutes of Health, Bethesda,Maryland 20892, USA;

    Genomics & Immunity, NIAMS, NCI, National Institutes of Health, Bethesda,Maryland 20892, USA;

    Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA;

    Laboratory of Genome Integrity, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA,Howard Hughes Medical Institute, The Rockefeller University,New York, New York 10065, USA;

    Genomics & Immunity, NIAMS, NCI, National Institutes of Health, Bethesda,Maryland 20892, USA,Center of Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA;

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