Nucleotide excision repair is impaired by binding of transcription factors to DNA
Nucleotide excision repair is impaired by binding of transcription factors to DNA
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DOI：
10.1038/nature17661
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发表时间：
2016-04-14
期刊：
影响因子：
64.8
通讯作者：
Lopez-Bigas, Nuria
中科院分区：
文献类型：
--
作者：
Sabarinathan, Radhakrishnan;Mularoni, Loris;Lopez-Bigas, Nuria
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差异，体细胞突变率在整个基因组中似乎存在很大差异（2-5）。然而，可能影响局部突变率的其他变量是未知的，例如dna结合蛋白的作用。在这里，我们证明了黑素瘤的体细胞突变率在活性转录因子结合位点和核小体嵌入的DNA上高度增加，与它们的侧翼区域相比。利用最近可用的切除修复测序（XR-seq）数据(6)，我们发现这些位点较高的突变率是由核苷酸切除修复（NER）活性水平的降低引起的。我们的工作表明，DNA结合蛋白干扰NER机制，导致蛋白质结合位点的DNA突变率增加。这一发现对我们理解突变和DNA修复过程以及识别癌症驱动突变具有重要意义。
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.