State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Department of Chemical Biology and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China.
Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China.
Angew Chem Int Ed Engl. 2016 Nov 7;55(46):14246-14249. doi: 10.1002/anie.201607380. Epub 2016 Oct 13.
Cisplatin, one of the most widely used anticancer drugs, crosslinks DNA and ultimately induces cell death. However, the genomic pattern of cisplatin-DNA adducts has remained unknown owing to the lack of a reliable and sensitive genome-wide method. Herein we present "cisplatin-seq" to identify genome-wide cisplatin crosslinking sites at base resolution. Cisplatin-seq reveals that mitochondrial DNA is a preferred target of cisplatin. For nuclear genomes, cisplatin-DNA adducts are enriched within promoters and regions harboring transcription termination sites. While the density of GG dinucleotides determines the initial crosslinking of cisplatin, binding of proteins to the genome largely contributes to the accumulative pattern of cisplatin-DNA adducts.
顺铂是最广泛使用的抗癌药物之一,它能使 DNA 链交联,最终导致细胞死亡。然而,由于缺乏可靠和敏感的全基因组方法,顺铂-DNA 加合物的基因组模式仍然未知。在此,我们提出“顺铂测序”(cisplatin-seq)以碱基分辨率鉴定全基因组顺铂交联位点。顺铂测序揭示了线粒体 DNA 是顺铂的首选靶标。对于核基因组,顺铂-DNA 加合物在内含子和含有转录终止位点的区域富集。虽然 GG 二核苷酸的密度决定了顺铂的初始交联,但蛋白质与基因组的结合在很大程度上导致了顺铂-DNA 加合物的累积模式。