Differential ETS1 binding to T:G mismatches within a CpG dinucleotide contributes to C-to-T somatic mutation rate of the IDH2 hotspot at codon Arg140.
Differential ETS1 binding to T:G mismatches within a CpG dinucleotide contributes to C-to-T somatic mutation rate of the IDH2 hotspot at codon Arg140.
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DOI：
10.1016/j.dnarep.2022.103306
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发表时间：
2022-05
期刊：
影响因子：
3.8
通讯作者：
Cheng, Xiaodong
中科院分区：
文献类型：
--
作者：
Yang, Jie;Gupta, Esha;Horton, John R.;Blumenthal, Robert M.;Zhang, Xing;Cheng, Xiaodong
胞嘧啶至胸腺嘧啶（C>T）体细胞突变在某些类型的癌症中高度富集，并且最常见地在CpG二核苷酸的情况下通过5-甲基胞嘧啶（5 mC）脱氨基至胸腺嘧啶而发生。理论上，相对链上的两个5 mC核苷酸的脱氨基应以相等的速率发生。在大多数情况下，产生的T：G或G：T错配可以通过胸腺嘧啶DNA糖基化酶活性修复。然而，虽然一些热点相关的CpG突变具有大约相同数量的突变，这些突变是由CpG二核苷酸中的C>T或G>A引起的，但许多突变显示出链偏好，偏向第一个碱基对的C>T或第二个碱基对的G>A。使用IDH 2 Arg 140密码子作为案例研究，我们表明，在密码子特异性CpG位点的两种可能的T：G错配对转录因子ETS 1结合亲和力有不同的影响，差异影响修复酶（MBD 4）对脱氨基引起的T：G错配的访问。因此，我们的研究提供了一个合理的机制，排除修复酶的差异结合的转录因子影响的速度，其中发生的先行对链突变。
Cytosine to thymine (C>T) somatic mutation is highly enriched in certain types of cancer, and most commonly occurs via deamination of a 5-methylcytosine (5mC) to thymine, in the context of a CpG dinucleotide. In theory, deamination should occur at equal rates to both 5mC nucleotides on opposite strands. In most cases, the resulting T:G or G:T mismatch can be repaired by thymine DNA glycosylase activities. However, while some hotspot-associated CpG mutations have approximately equal numbers of mutations that resulted either from C>T or G>A in a CpG dinucleotide, many showed strand bias, being skewed toward C>T of the first base pair or G>A of the second base pair. Using the IDH2 Arg140 codon as a case study, we show that the two possible T:G mismatches at the codon-specific CpG site have differing effects on transcription factor ETS1 binding affinity, differentially affecting access of a repair enzyme (MBD4) to the deamination-caused T:G mismatch. Our study thus provides a plausible mechanism for exclusion of repair enzymes by the differential binding of transcription factors affecting the rate at which the antecedent opposite-strand mutations occur.
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