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  3. Pt-seq unveils the genomic binding pattern of platinum-based drugs

Pt-seq unveils the genomic binding pattern of platinum-based drugs

  • Sci Adv. 2025 Oct 31;11(44):eadx6809. doi: 10.1126/sciadv.adx6809.
Chuyun Shao 1 2,  Mingyang Li 1 3,  Liuyi Liu 4,  Dongsheng Bai 1,  Jinmin Yang 1,  Cong Liu 1,  Linxiang Cai 4,  Xiaoyong Wang 5,  Jinying Peng 1,  Zijian Guo 4,  Chengqi Yi 1 3 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing, China.
  • 2 Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
  • 3 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
  • 4 State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
  • 6 Department of Chemical Biology and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
PMID: 41160705 DOI: 10.1126/sciadv.adx6809
Abstract

Platinum-based drugs (Pt drugs) are widely used in Cancer chemotherapy, yet their genome-wide binding patterns remain incompletely understood. Here, we present Pt Sequencing (Pt-seq), an antibody-assisted, genome-wide method for mapping Pt-DNA adducts at single-base resolution. By using exo- and endonucleases to remove background, Pt-seq enables robust and sensitive profiling of binding sites for cisplatin, oxaliplatin, lobaplatin, and a Pt(IV) complex. Using Pt-seq, we identified tens to hundreds of binding clusters that are 10 to 20 kilobases in median length and highly consistent among different drugs, predominantly localizing to centromeric and ribosomal DNA regions. In cisplatin-resistant cells, we found significantly reduced binding within these regions. Moreover, we found that mutations in Cancer cells can generate previously unidentified binding sites. On this basis, we demonstrated that ICR-191, an acridine orange compound capable of inducing G insertions, enhances cisplatin-DNA binding and sensitizes cells to cisplatin. Collectively, Pt-seq sensitively profiles Pt-DNA interactions and deepens our understanding of the genome-wide effect of chemotherapeutic drugs.

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