Base damage, local sequence context and TP53 mutation hotspots: a molecular dynamics study of benzo[a]pyrene induced DNA distortion and mutability.
Base damage, local sequence context and TP53 mutation hotspots: a molecular dynamics study of benzo[a]pyrene induced DNA distortion and mutability.
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DOI：
10.1093/nar/gkv910
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发表时间：
2015-10-30
影响因子：
14.9
通讯作者：
Lewis PD
中科院分区：
文献类型：
--
作者：
Menzies GE;Reed SH;Brancale A;Lewis PD
肺肿瘤中TP53肿瘤抑制基因的突变模式与其他癌症类型不同，具有更高的G：C>T：A颠换频率。这种不同突变模式的病因仍然未知。苯并[a]芘二醇环氧化物（BPDE）是一种强效香烟烟雾致癌物，在TP53 CpG突变热点位点（包括密码子157、158、245、248和273）形成鸟嘌呤加合物。我们对BPDE加合的TP53双链体序列进行了分子建模，以确定加合物引起的局部扭曲程度，这可能影响核苷酸切除修复的能力。我们发现BPDE加合密码子157比其他TP53 G：C>T：A热点位点具有更大的结构畸变，并且更远离相邻碱基的序列背景必须影响局部畸变。使用吸烟者和非吸烟者肺癌的TP53三核苷酸突变特征，我们进一步表明密码子157和273在吸烟者中具有最高的突变概率。结合这些信息和加合物结构数据，我们预测吸烟者肺肿瘤中密码子157处的G：C>T：A突变主要由BPDE引起。我们的研究结果提供了深入了解不同的DNA序列背景如何在诱变剂加合物位点显示DNA畸变的变异性，这些变异性可能会损害在充分表征的癌症相关突变热点的DNA修复。
The mutational pattern for the TP53 tumour suppressor gene in lung tumours differs to other cancer types by having a higher frequency of G:C>T:A transversions. The aetiology of this differing mutation pattern is still unknown. Benzo[a]pyrene,diol epoxide (BPDE) is a potent cigarette smoke carcinogen that forms guanine adducts at TP53 CpG mutation hotspot sites including codons 157, 158, 245, 248 and 273. We performed molecular modelling of BPDE-adducted TP53 duplex sequences to determine the degree of local distortion caused by adducts which could influence the ability of nucleotide excision repair. We show that BPDE adducted codon 157 has greater structural distortion than other TP53 G:C>T:A hotspot sites and that sequence context more distal to adjacent bases must influence local distortion. Using TP53 trinucleotide mutation signatures for lung cancer in smokers and non-smokers we further show that codons 157 and 273 have the highest mutation probability in smokers. Combining this information with adduct structural data we predict that G:C>T:A mutations at codon 157 in lung tumours of smokers are predominantly caused by BPDE. Our results provide insight into how different DNA sequence contexts show variability in DNA distortion at mutagen adduct sites that could compromise DNA repair at well characterized cancer related mutation hotspots.