Mutagenic consequences of cytosine alterations site-specifically embedded in the human genome.
Mutagenic consequences of cytosine alterations site-specifically embedded in the human genome.
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DOI：
10.1186/s41021-016-0045-9
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Yasui M
中科院分区：
文献类型：
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作者：
Sassa A;Kanemaru Y;Kamoshita N;Honma M;Yasui M
CpG二核苷酸中的胞嘧啶残基通常经历各种类型的修饰，如甲基化、脱氨基和卤化。这些类型的修饰可以是促突变的，并且可以有助于在细胞中形成突变热点。为了分析人类基因组中DNA修饰诱导的突变，我们最近开发了一种用于追踪靶向诱变中的DNA加合物的系统（TATAM）。在该系统中，将修饰/损伤的碱基位点特异性地引入人淋巴母细胞中胸苷激酶基因的内含子4中。为了进一步理解胞嘧啶修饰的诱变，我们直接将不同类型的改变的胞嘧啶残基引入基因组中，并使用TATAM系统研究其基因组后果。在基因组中，胸腺嘧啶和5-溴尿嘧啶与鸟嘌呤的配对（分别由5-甲基胞嘧啶和5-溴胞嘧啶的脱氨基作用产生）与尿嘧啶与鸟嘌呤的配对（由胞嘧啶残基的脱氨基作用产生）相比具有高度促突变性。5-甲基胞嘧啶和5-溴胞嘧啶的脱氨基作用而不是正常胞嘧啶的脱氨基作用显著增强了人类基因组中的致突变潜力。
Cytosine residues in CpG dinucleotides often undergo various types of modification, such as methylation, deamination, and halogenation. These types of modifications can be pro-mutagenic and can contribute to the formation of mutational hotspots in cells. To analyze mutations induced by DNA modifications in the human genome, we recently developed a system for tracing DNA adducts in targeted mutagenesis (TATAM). In this system, a modified/damaged base is site-specifically introduced into intron 4 of thymidine kinase genes in human lymphoblastoid cells. To further the understanding of the mutagenesis of cytosine modification, we directly introduced different types of altered cytosine residues into the genome and investigated their genomic consequences using the TATAM system. In the genome, the pairing of thymine and 5-bromouracil with guanine, resulting from the deamination of 5-methylcytosine and 5-bromocytosine, respectively, was highly pro-mutagenic compared with the pairing of uracil with guanine, resulting from the deamination of cytosine residues. The deamination of 5-methylcytosine and 5-bromocytosine rather than that of normal cytosine dramatically enhances the mutagenic potential in the human genome.