然而，研究团队目前缺乏关于该病变结构的直接信息。在这项工作中，研究小组结合质谱和核磁共振波谱来阐明大肠杆菌素- DNA ICL的特异性和结构。小组发现大肠杆菌蛋白在腺嘌呤和胸腺嘧啶丰富的DNA的小槽内烷基化，解释了突变特征的起源。出乎意料的是，该团队发现化学上不稳定的大肠杆菌蛋白中心基序介导了交联的序列特异性。通过直接阐明大肠杆菌蛋白与DNA的相互作用，这项工作增强了他们对这种与癌症相关的肠道细菌天然产物的结构和遗传毒性机制的理解。
据悉，越来越多的证据表明，化学上不稳定、破坏DNA的肠道细菌天然产物大肠杆菌素与结直肠癌有关，包括鉴定出被认为是由大肠杆菌素-DNA链间交联（ICLs）引起的突变特征。
附：英文原文
Title: The specificity and structure of DNA cross-linking by the gut bacterial genotoxin colibactin
Author: Erik S. Carlson, Raphael Haslecker, Chiara Lecchi, Miguel A. Aguilar Ramos, Vyshnavi Vennelakanti, Linda Honaker, Alessia Stornetta, Estela S. Millán, Bruce A. Johnson, Heather J. Kulik, Silvia Balbo, Peter W. Villalta, Victoria M. D’Souza, Emily P. Balskus
Issue&Volume: 2025-12-04
Abstract: 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.
DOI: ady3571
Source: https://www.science.org/doi/10.1126/science.ady3571