The major mechanism of melanoma mutations is based on deamination of cytosine in pyrimidine dimers as determined by circle damage sequencing.
The major mechanism of melanoma mutations is based on deamination of cytosine in pyrimidine dimers as determined by circle damage sequencing.
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DOI：
10.1126/sciadv.abi6508
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发表时间：
2021-07
期刊：
影响因子：
13.6
通讯作者：
Pfeifer GP
中科院分区：
文献类型：
--
作者：
Jin SG;Pettinga D;Johnson J;Li P;Pfeifer GP
具有脱氨基胞嘧啶的嘧啶二聚体的序列特异性与黑色素瘤中的突变高度相似。阳光相关的黑色素瘤携带独特的C到T突变签名。UVB辐射诱导环丁烷嘧啶二聚体（CPD）作为DNA损伤的主要形式，但CPD如何引起突变的机制尚不清楚。为了以单碱基分辨率全基因组定位CPD，我们开发了环损伤测序（circle-damage-seq）方法。在人类细胞中，CPD优先在四核苷酸序列背景下（5′-Py-T<>Py-T/A）形成，但这本身并不能解释肿瘤突变模式。为了测试突变是否出现在CPD的胞嘧啶脱氨基，我们专门映射UVB诱导的胞嘧啶脱氨基CPD。转录起始位点（TSS）受到保护，从CPD和脱氨基CPD，但这两个病变富集立即上游的TSS，这表明结合转录因子的突变促进作用。最重要的是，脱氨基CPD的基因组二核苷酸和三核苷酸序列特异性与黑色素瘤的突出突变特征相匹配。我们的数据确定胞嘧啶脱氨基CPD作为导致黑色素瘤突变的主要预致突变病变。
The sequence specificity of pyrimidine dimers with deaminated cytosines is highly similar to that of mutations in melanoma. Sunlight-associated melanomas carry a unique C-to-T mutation signature. UVB radiation induces cyclobutane pyrimidine dimers (CPDs) as the major form of DNA damage, but the mechanism of how CPDs cause mutations is unclear. To map CPDs at single-base resolution genome wide, we developed the circle damage sequencing (circle-damage-seq) method. In human cells, CPDs form preferentially in a tetranucleotide sequence context (5′-Py-T<>Py-T/A), but this alone does not explain the tumor mutation patterns. To test whether mutations arise at CPDs by cytosine deamination, we specifically mapped UVB-induced cytosine-deaminated CPDs. Transcription start sites (TSSs) were protected from CPDs and deaminated CPDs, but both lesions were enriched immediately upstream of the TSS, suggesting a mutation-promoting role of bound transcription factors. Most importantly, the genomic dinucleotide and trinucleotide sequence specificity of deaminated CPDs matched the prominent mutation signature of melanomas. Our data identify the cytosine-deaminated CPD as the leading premutagenic lesion responsible for mutations in melanomas.
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影响因子：
16.6
作者：
Mao, Peng;Brown, Alexander J.;Wyrick, John J.
通讯作者：
Wyrick, John J.
DOI：
10.1126/science.aao3130
发表时间：
2017-10-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Drost J;van Boxtel R;Blokzijl F;Mizutani T;Sasaki N;Sasselli V;de Ligt J;Behjati S;Grolleman JE;van Wezel T;Nik-Zainal S;Kuiper RP;Cuppen E;Clevers H
通讯作者：
Clevers H
DOI：
10.1073/pnas.1706522114
发表时间：
2017-06-27
影响因子：
11.1
作者：
Hu, Jinchuan;Adebali, Ogun;Sancar, Aziz
通讯作者：
Sancar, Aziz
影响因子：
2.9
作者：
JIANG, N;TAYLOR, JS
通讯作者：
TAYLOR, JS
影响因子：
16
作者：
Canela A;Sridharan S;Sciascia N;Tubbs A;Meltzer P;Sleckman BP;Nussenzweig A
通讯作者：
Nussenzweig A