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首页> 外文期刊>Journal of Molecular Biology >THE MUTAGENIC PROCESSING OF PSORALEN PHOTOLESIONS LEAVES A HIGHLY SPECIFIC SIGNATURE AT AN ENDOGENOUS HUMAN LOCUS
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THE MUTAGENIC PROCESSING OF PSORALEN PHOTOLESIONS LEAVES A HIGHLY SPECIFIC SIGNATURE AT AN ENDOGENOUS HUMAN LOCUS

机译：内源性人类位置上PSORALEN光致突变的突变处理留下了高度特定的特征

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To assess the role of a given genotoxic agent in the etiology of human cancers, it is useful to establish the mutational specificity of this agent. The aim of this study was to investigate whether the processing of psoralen photolesions, interstrand cross-links (CL) and monoadducts (MA), leaves a specific molecular signature in the mutational events produced at an endogenous locus, HPRT. Human lymphoblasts were treated by 4,5',8-trimethylpsoralen (Me(3)Pso) in association with a double irradiation protocol (365 plus 365 nm) which allows us to increase the proportion of CL for a given constant number of total photoadducts. The molecular spectrum of mutations at the HPRT locus induced in these conditions was compared to the previously reported spectra of mutations induced by the same psoralen in combination with a single irradiation of either 365 nm (induction of MA and a low proportion of CL) or 405 nm (producing almost exclusively MA). In all treatment conditions, base substitutions constitute the major type of Me(3)Pso photoinduced mutations. The majority of base substitutions involve a T residue preferably within a 5'-TpA sequence which corresponds to the favoured sites of psoralen photoadducts. In other words, the Me(3)Pso photolesions induce at the endogenous HPRT locus a highly specific signature. Moreover, base substitutions have been essentially found in the non-transcribed strand of the HPRT gene suggesting that the psoralen photolesions are preferentially removed from the transcribed strand. In spite of the considerable difference between the proportion of lesions of both types (CL or MA) induced in different treatment conditions, the kind of mutations and their sequence distribution are similar suggesting that the mutagenic processing of psoralen CL and MA is similar at least for the steps resulting in base substitutions. (C) 1995 Academic Press Limited [References: 36]
机译：为了评估给定的遗传毒性药物在人类癌症病因中的作用，建立该药物的突变特异性是有用的。这项研究的目的是调查补骨脂素光损伤，链间交联（CL）和单加合物（MA）的加工是否在内源基因座HPRT产生的突变事件中留下特定的分子特征。人类淋巴母细胞通过4,5'，8-三甲基补骨脂素（Me（3）Pso）结合双辐照协议（365加365 nm）进行处理，这使我们能够在给定恒定数量的总光加合物中增加CL的比例。将在这些条件下诱导的HPRT基因座突变的分子光谱与先前报道的同一补骨脂素结合365 nm（MA的诱导和低比例的CL的单次照射）或405的单次照射诱导的突变的光谱进行比较nm（几乎只生产MA）。在所有治疗条件下，碱基取代构成Me（3）Pso光诱导突变的主要类型。大多数碱基取代涉及T残基，该残基优选在5'-TpA序列内，其对应于补骨脂素光加合物的有利位点。换句话说，Me（3）Pso光损伤在内源性HPRT基因座上诱导了高度特异性的签名。此外，已经基本在HPRT基因的非转录链中发现了碱基取代，这表明补骨脂素光损伤优先从转录链中去除。尽管在不同治疗条件下诱发的两种类型（CL或MA）病变的比例之间存在显着差异，但突变的种类及其序列分布相似，这表明补骨脂素CL和MA的诱变过程至少在以下方面相似。导致碱基替换的步骤。 （C）1995 Academic Press Limited [参考：36]

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