Cisplatin DNA damage and repair maps of the human genome at single-nucleotide resolution

Jinchuan Hu, Jason D. Lieb, Aziz Sancar, Sheera Adar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

132 Scopus citations

Abstract

Cisplatin is a major anticancer drug that kills cancer cells by damaging their DNA. Cancer cells cope with the drug by removal of the damages with nucleotide excision repair. We have developed methods to measure cisplatin adduct formation and its repair at single-nucleotide resolution. "Damage-seq" relies on the replication-blocking properties of the bulky base lesions to precisely map their location. "XR-seq" independently maps the removal of these damages by capturing and sequencing the excised oligomer released during repair. The damage and repair maps we generated reveal that damage distribution is essentially uniform and is dictated mostly by the underlying sequence. In contrast, cisplatin repair is heterogeneous in the genome and is affected by multiple factors including transcription and chromatin states. Thus, the overall effect of damages in the genome is primarily driven not by damage formation but by the repair efficiency. The combination of the Damageseq and XR-seq methods has the potential for developing novel cancer therapeutic strategies.

Original languageAmerican English
Pages (from-to)11507-11512
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number41
DOIs
StatePublished - 11 Oct 2016

Bibliographical note

Funding Information:
We thank Dr. Sebastian Pott for fruitful discussion and advice. This work was supported by NIH Grant GM118102.

Keywords

  • Cancer
  • Chemotherapy
  • Damage-seq
  • Nucleotide excision repair
  • XR-seq

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