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Nucleotide excision repair is impaired by binding of transcription factors to DNA

机译：转录因子与DNA的结合会破坏核苷酸的切除修复

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摘要

Somatic mutations are the driving force of cancer genome evolution(1). The rate of somatic mutations appears to be greatly variable across the genome due to variations in chromatin organization, DNA accessibility and replication timing(2-5). However, other variables that may influence the mutation rate locally are unknown, such as a role for DNA-binding proteins, for example. Here we demonstrate that the rate of somatic mutations in melanomas is highly increased at active transcription factor binding sites and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data(6), we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of DNA mutations at the protein binding sites. This finding has important implications for our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.
机译：体细胞突变是癌症基因组进化的驱动力（1）。由于染色质组织，DNA可及性和复制时间的变化，体细胞突变的速率似乎在整个基因组中有很大的差异（2-5）。但是，尚不清楚其他可能局部影响突变率的变量，例如DNA结合蛋白的作用。在这里，我们证明，与它们的侧翼区域相比，黑色素瘤中的体细胞突变率在活性转录因子结合位点和核小体包埋的DNA处高度增加。使用最近可用的切除修复测序（XR-seq）数据（6），我们显示这些位点的较高突变率是由核苷酸切除修复（NER）活性水平降低引起的。我们的工作表明，DNA结合蛋白会干扰NER机制，从而导致蛋白结合位点的DNA突变率增加。这一发现对我们对突变和DNA修复过程的理解以及对癌症驱动突变的鉴定具有重要意义。

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  • 来源
    《Nature》 |2016年第7598期|264-267|共4页
  • 作者

    Sabarinathan Radhakrishnan; Mularoni Loris; Deu-Pons Jordi; Gonzalez-Perez Abel; Lopez-Bigas Nuria;

  • 作者单位

    IMIM Hosp del Mar Med Res Inst, Res Program Biomed Informat, Doctor Aiguader 88, Barcelona 08003, Spain|Univ Pompeu Fabra, Doctor Aiguader 88, Barcelona 08003, Spain;

    IMIM Hosp del Mar Med Res Inst, Res Program Biomed Informat, Doctor Aiguader 88, Barcelona 08003, Spain|Univ Pompeu Fabra, Doctor Aiguader 88, Barcelona 08003, Spain;

    IMIM Hosp del Mar Med Res Inst, Res Program Biomed Informat, Doctor Aiguader 88, Barcelona 08003, Spain|Univ Pompeu Fabra, Doctor Aiguader 88, Barcelona 08003, Spain;

    IMIM Hosp del Mar Med Res Inst, Res Program Biomed Informat, Doctor Aiguader 88, Barcelona 08003, Spain|Univ Pompeu Fabra, Doctor Aiguader 88, Barcelona 08003, Spain;

    IMIM Hosp del Mar Med Res Inst, Res Program Biomed Informat, Doctor Aiguader 88, Barcelona 08003, Spain|Univ Pompeu Fabra, Doctor Aiguader 88, Barcelona 08003, Spain|ICREA, Passeig Lluis Co 23, Barcelona 08010, Spain;

  • 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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  • 正文语种 eng
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