Genome-wide alterations of uracil distribution patterns in human DNA upon chemotherapeutic treatments.
Genome-wide alterations of uracil distribution patterns in human DNA upon chemotherapeutic treatments.
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DOI：
10.7554/elife.60498
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发表时间：
2020-09-21
期刊：
影响因子：
7.7
通讯作者：
Vértessy BG
中科院分区：
文献类型：
--
作者：
Pálinkás HL;Békési A;Róna G;Pongor L;Papp G;Tihanyi G;Holub E;Póti Á;Gemma C;Ali S;Morten MJ;Rothenberg E;Pagano M;Szűts D;Győrffy B;Vértessy BG
许多抗癌药物干扰胸苷酸的生物合成，并导致基因组尿嘧啶掺入，有助于其抗增殖作用。尽管如此，它还没有被表征，如果尿嘧啶双链有任何位置偏好。在这里，我们的目的是揭示在药物治疗后，来自HCT 116的人癌细胞系模型中尿嘧啶模式的全基因组改变。我们开发了一种简单的U-DNA测序方法（U-DNA-Seq），该方法与原位超分辨率成像相结合。使用一种新的强大的分析管道，我们发现了广泛的区域，在处理和未处理的细胞中尿嘧啶的出现概率增加。与染色质标记物和其他基因组特征的相关性表明，未处理的细胞在后期复制的组成性异染色质区中具有尿嘧啶，而药物处理诱导掺入的尿嘧啶向通常更具活性/功能的片段转移。通过dSTORM显微镜的共定位研究证实了数据。这种方法可以应用于研究基因组尿嘧啶的动态时空性质。
Numerous anti-cancer drugs perturb thymidylate biosynthesis and lead to genomic uracil incorporation contributing to their antiproliferative effect. Still, it is not yet characterized if uracil incorporations have any positional preference. Here, we aimed to uncover genome-wide alterations in uracil pattern upon drug treatments in human cancer cell line models derived from HCT116. We developed a straightforward U-DNA sequencing method (U-DNA-Seq) that was combined with in situ super-resolution imaging. Using a novel robust analysis pipeline, we found broad regions with elevated probability of uracil occurrence both in treated and non-treated cells. Correlation with chromatin markers and other genomic features shows that non-treated cells possess uracil in the late replicating constitutive heterochromatic regions, while drug treatment induced a shift of incorporated uracil towards segments that are normally more active/functional. Data were corroborated by colocalization studies via dSTORM microscopy. This approach can be applied to study the dynamic spatio-temporal nature of genomic uracil.
影响因子：
8.8
作者：
Blackledge, G
通讯作者：
Blackledge, G