Mutagen-Specific Mutation Signature Determines Global microRNA Binding

Micro-RNAs (miRNAs) are small non-coding RNAs that regulate gene products at the post-transcriptional level. It is thought that loss of cell regulation by miRNAs supports cancer development. Based on whole genome sequencing of a melanoma tumor, we predict, using three different computational algorithms, that the melanoma somatic mutations globally reduce binding of miRNAs to the mutated 3′UTRs. This phenomenon reflects the nature of the characteristic UV-induced mutation, C-to-T. Furthermore, we show that seed regions are enriched with Guanine, thus rendering miRNAs prone to reduced binding to UV-mutated 3′UTRs. Accordingly, mutation patterns in non UV-induced malignancies e.g. lung cancer and leukemia do not yield similar predictions. It is suggested that UV-induced disruption of miRNA-mediated gene regulation plays a carcinogenic role. Remarkably, dark-skinned populations have significantly higher GC content in 3′UTR SNPs than light-skinned populations, which implies on evolutionary pressure to preserve regulation by trans-acting oligonucleotides under conditions with excess UV radiation.

微小RNA（Micro-RNAs, miRNAs）是一类小型非编码RNA，可在转录后水平调控基因产物的表达。现有研究表明，miRNAs介导的细胞调控功能缺失会促进癌症发生发展。本研究基于某黑色素瘤的全基因组测序数据，采用三种不同的计算算法开展预测，结果显示黑色素瘤体细胞突变会在全局范围内削弱miRNAs与突变型3'非翻译区（3′Untranslated Regions, 3′UTRs）的结合能力。该现象与特征性紫外线诱导突变——C到T（C-to-T）的突变特性相符。进一步研究发现，miRNA的种子区域富含鸟嘌呤（Guanine），这使得miRNAs更易出现与紫外线诱导突变的3'UTRs结合能力下降的情况。相应地，在非紫外线诱导的恶性肿瘤（如肺癌、白血病）中，并未得到类似的预测结果。本研究提示，紫外线诱导的miRNA介导基因调控紊乱可发挥致癌作用。值得注意的是，深色皮肤人群的3'UTR单核苷酸多态性（Single Nucleotide Polymorphisms, SNPs）中GC含量显著高于浅色皮肤人群，这暗示在紫外线辐射过量的环境中，机体存在维持反式作用寡核苷酸调控功能的进化压力。