The Fanconi anemia pathway repairs colibactin-induced DNA interstrand cross-links

Maria Altshuller, Xu He, Elliot J. MacKrell, Kevin M. Wernke, Yougant Airan, Joel W. H. Wong, Selene Sellés-Baiget, Ting-Yu Wang, Tsui-Fen Chou, Julien P. Duxin, Emily P. Balskus, Seth B. Herzon and Daniel R. Semlow ()
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Maria Altshuller: California Institute of Technology, Division of Chemistry and Chemical Engineering
Xu He: California Institute of Technology, Division of Chemistry and Chemical Engineering
Elliot J. MacKrell: California Institute of Technology, Division of Chemistry and Chemical Engineering
Kevin M. Wernke: Yale University, Department of Chemistry
Yougant Airan: Yale University, Department of Chemistry
Joel W. H. Wong: Harvard University, Department of Chemistry and Chemical Biology
Selene Sellés-Baiget: University of Copenhagen, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences
Ting-Yu Wang: California Institute of Technology, Division of Biology and Biological Engineering
Tsui-Fen Chou: California Institute of Technology, Division of Biology and Biological Engineering
Julien P. Duxin: University of Copenhagen, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences
Emily P. Balskus: Harvard University, Department of Chemistry and Chemical Biology
Seth B. Herzon: Yale University, Department of Chemistry
Daniel R. Semlow: California Institute of Technology, Division of Chemistry and Chemical Engineering

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Colibactin is a secondary metabolite produced by bacteria present in the human gut and is implicated in the development of colorectal cancer. This genotoxin alkylates deoxyadenosines on opposite strands of host cell DNA to produce DNA interstrand cross-links. While cells have evolved multiple mechanisms to resolve (“unhook”) interstrand cross-links, little is known about which of these pathways promote resistance to colibactin. Here, we use Xenopus egg extracts to investigate replication-coupled repair of colibactin-induced interstrand cross-links. We show that replication fork stalling at a colibactin-induced interstrand cross-link activates the Fanconi anemia interstrand cross-link repair pathway, which unhooks the interstrand cross-link through nucleolytic incisions. These incisions generate a DNA double-strand break intermediate in one sister chromatid, which can be repaired by homologous recombination, and a monoadduct (“interstrand cross-link remnant”) in the other. Translesion synthesis past the colibactin-induced interstrand cross-link remnant depends on Pol η and the Pol κ-REV1-Pol ζ polymerase complex and introduces predominantly T>A point mutations at the sites of colibactin alkylation. Taken together, our work provides a molecular framework for understanding how cells tolerate a naturally occurring and clinically relevant interstrand cross-link.

Date: 2025
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DOI: 10.1038/s41467-025-65606-1

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