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Base-Resolution Analysis of Cisplatin-DNA Adducts at the Genome Scale
Xiaoting Shu1,2, Xushen Xiong1,2, Jinghui Song1
1State 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.
Abstract:
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.
Insights
Cisplatin anticancer drug adducts were mapped genome-wide using cisplatin-seq. This method revealed mitochondrial DNA as a preferred target, with nuclear adducts accumulating in promoters and transcription termination sites.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- Cisplatin is a crucial anticancer drug that induces cell death by crosslinking DNA.
- Understanding the genomic distribution of cisplatin-DNA adducts is essential for optimizing cancer therapy.
- Previous methods lacked the sensitivity and resolution for genome-wide adduct mapping.
Purpose of the Study:
- To develop a reliable and sensitive genome-wide method for identifying cisplatin-DNA crosslinking sites at base resolution.
- To determine the genomic distribution and enrichment patterns of cisplatin-DNA adducts.
- To elucidate the factors influencing cisplatin-DNA adduct accumulation.
Main Methods:
- Development and application of a novel technique named "cisplatin-seq".
- Genome-wide identification of cisplatin crosslinking sites with base-pair resolution.
- Analysis of adduct distribution in both mitochondrial and nuclear genomes.
Main Results:
- Mitochondrial DNA was identified as a preferred target for cisplatin.
- In nuclear genomes, cisplatin-DNA adducts showed enrichment in promoter regions and transcription termination sites.
- The density of GG dinucleotides influences initial cisplatin crosslinking, while protein-genome binding significantly contributes to adduct accumulation.
Conclusions:
- Cisplatin-seq provides a powerful tool for mapping DNA adducts genome-wide.
- Cisplatin exhibits distinct targeting preferences in mitochondrial versus nuclear DNA.
- Both DNA sequence and protein interactions dictate the final genomic landscape of cisplatin adducts, offering insights into drug efficacy and resistance.
