ETS transcription factors induce a unique UV damage signature that drives recurrent mutagenesis in melanoma
ETS transcription factors induce a unique UV damage signature that drives recurrent mutagenesis in melanoma
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DOI：
10.1038/s41467-018-05064-0
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发表时间：
2018-07-06
影响因子：
16.6
通讯作者：
Wyrick, John J.
中科院分区：
文献类型：
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作者：
Mao, Peng;Brown, Alexander J.;Wyrick, John J.
复发性突变通常与黑色素瘤中的转录因子（TF）结合位点（TFBS）相关，但驱动TFBS突变的机制尚不清楚。在这里，我们使用一种称为CPD-seq的方法来绘制单核苷酸分辨率下UV诱导的环丁烷嘧啶二聚体（CPD）在人类基因组中的分布。我们的研究结果表明，CPD病变在活动TFBS升高，这种效应主要是由于E26转化特异性（ETS）TF。我们发现，ETS TF诱导CPD热点的独特签名，与黑色素瘤中的复发突变高度相关，尽管在这些位点具有高修复活性。ETS 1蛋白使其DNA结合靶在体外对UV损伤极其敏感，这是由于结合诱导的DNA结构扰动有利于CPD形成。这些发现定义了一种机制，负责复发性突变的黑色素瘤，并揭示了DNA结合ETS TF是固有的诱变性在紫外线暴露的细胞。
Recurrent mutations are frequently associated with transcription factor (TF) binding sites (TFBS) in melanoma, but the mechanism driving mutagenesis at TFBS is unclear. Here, we use a method called CPD-seq to map the distribution of UV-induced cyclobutane pyrimidine dimers (CPDs) across the human genome at single nucleotide resolution. Our results indicate that CPD lesions are elevated at active TFBS, an effect that is primarily due to E26 transformation-specific (ETS) TFs. We show that ETS TFs induce a unique signature of CPD hotspots that are highly correlated with recurrent mutations in melanomas, despite high repair activity at these sites. ETS1 protein renders its DNA binding targets extremely susceptible to UV damage in vitro, due to binding-induced perturbations in the DNA structure that favor CPD formation. These findings define a mechanism responsible for recurrent mutations in melanoma and reveal that DNA binding by ETS TFs is inherently mutagenic in UV-exposed cells.