Click-code-seq reveals strand biases of DNA oxidation and depurination in human genome
Open accessPublished version of a preprint
Abstract
DNA modifications drive aging, neurodegeneration, carcinogenesis and chemotherapy drug action. Accurate mapping of diverse DNA modifications with single-nucleotide precision in complex genomes remains challenging. We upgraded click-code-seq, a click-chemistry-aided DNA-modification mapping strategy, to enable its first application for sequencing oxidation and depurination in the human genome. We developed a companion fluorescence assay, click-fluoro-quant, to rapidly quantify common DNA modifications and novel adaptors to minimize false positives and assess modification frequency. We uncovered that endogenous DNA oxidation in a human cell line mirrors cancer mutational signatures linked to oxidative stress. The chemotherapy drug irofulven preferentially induces depurination in ApA dimers and promoters. Notably, oxidized guanines and apurinic sites, both irofulven induced and endogenous, are depleted in gene transcribed strands, with the strand bias increasing with gene expression. This work substantially advances click-code-seq for deciphering the impacts of key modifications in human DNA on cellular physiology and toxicological responses.
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- Authors
- Takhaveev, V., Püllen, N. J. L., Singh, N. K., Lefevre, L., Aghajani, E. A., Huber, S. M., Schauer, S., Gahlon, H. L., Poetsch, A. R., & Sturla, S. J.
- Affiliations
- ETH Zurich (CH)
- University of Zurich (CH)
- Nationales Centrum für Tumorerkrankungen Dresden (DE)
- Corresponding author
- Sturla, Shana J.
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2025-10-31
- Volume
- 22
- Issue
- 5
- Pages
- 716-727
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W4415731709
- Cited by
- 10
- References
- 10
- Citations by year
- 2026: 8 · 2025: 2
- FWCI
- 2.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Chemical Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (185020, 186332)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- DNA oxidation, depurination, DNA modification, strand bias, oxidative stress, mutational signatures, irofulven, apurinic sites, oxidized guanine, promoter, gene expression, human genome
- MeSH terms
- DNA, Humans, Oxidation-Reduction, Genome, Human, Oxidative Stress, Click Chemistry
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