The specificity and structure of DNA cross-linking by the gut bacterial genotoxin colibactin

• 成果类型: Article
• 署名作者: Carlson, Erik S.; Haslecker, Raphael; Lecchi, Chiara; Aguilar Ramos, Miguel A.; Vennelakanti, Vyshnavi; Honaker, Linda; Stornetta, Alessia; Millan, Estela S.; Johnson, Bruce A.; Kulik, Heather J.; Balbo, Silvia; Villalta, Peter W.; D'souza, Victoria M.; Balskus, Emily P.
• 署名单位: Harvard University; Harvard University; University of Minnesota System; University of Minnesota Twin Cities; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); City University of New York (CUNY) System; University of Minnesota System; University of Minnesota Twin Cities; Harvard University; Howard Hughes Medical Institute; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.ady3571
• 发表日期: 2025-12-04
• 页码: eady3571
• 关键词: molecular-orbital methods; double-strand breaks; gaussian-type basis; MINOR-GROOVE; protein; RECOGNITION; coli; CC-1065; nmr

摘要

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.