The specificity and structure of DNA cross-linking by the gut bacterial genotoxin colibactin
Accumulating evidence has connected the chemically unstable, DNA-damaging gut bacterial natural product colibactin to colorectal cancer, including the identification of mutational signatures that are thought to arise from colibactin-DNA interstrand cross-links (ICLs). However, we currently lack direct information regarding the structure of this lesion. In this work, we combined mass spectrometry and nuclear magnetic resonance spectroscopy to elucidate the specificity and structure of the colibactin-DNA ICL. We found that colibactin alkylates within the minor groove of adenine- and thymine-rich DNA, explaining the origins of mutational signatures. Unexpectedly, we discovered that the chemically unstable central motif of colibactin mediates the sequence specificity of cross-linking. By directly elucidating colibactin's interactions with DNA, this work enhances our understanding of the structure and genotoxic mechanisms of this cancer-linked gut bacterial natural product.
Authors
- Raphael Haslecker (ORCID: https://orcid.org/0000-0001-8001-9534)
- Peter W. Villalta (ORCID: https://orcid.org/0000-0002-0067-3083)
- Erik S. Carlson (ORCID: https://orcid.org/0000-0001-9134-1246)
- Vyshnavi Vennelakanti (ORCID: https://orcid.org/0000-0001-7677-2902)
- Heather Janine Kulik (ORCID: https://orcid.org/0000-0001-9342-0191)
- Bruce A. Johnson (ORCID: https://orcid.org/0000-0001-8445-5368)
- Victoria D′Souza (ORCID: https://orcid.org/0000-0002-5397-9481)
- Silvia Balbo (ORCID: https://orcid.org/0000-0002-7686-0504)
- Alessia Stornetta (ORCID: https://orcid.org/0000-0002-8287-9551)
- Emily P. Balskus (ORCID: https://orcid.org/0000-0001-5985-5714)
- Miguel A. Aguilar Ramos (ORCID: https://orcid.org/0000-0002-2537-8371)
- Chiara Lecchi (ORCID: https://orcid.org/0009-0009-0345-778X)
- Linda Honaker
- Estela S. Millán (ORCID: https://orcid.org/0009-0001-4096-853X)
Institutions
- Broad Institute (US)
- The Graduate Center, CUNY (US)
- University of Minnesota (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- CUNY Advanced Science Research Center (US)
- University of Minnesota Medical Center (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Science
- Published
- 2025-12-04
- DOI
- https://doi.org/10.1126/science.ady3571
- Citations
- 4
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.22