The human gut bacterial genotoxin colibactin alkylates DNA
Certain Escherichia coli strains residing in the human gut produce colibactin, a small-molecule genotoxin implicated in colorectal cancer pathogenesis. However, colibactin’s chemical structure and the molecular mechanism underlying its genotoxic effects have remained unknown for more than a decade....
| Main Authors: | , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
American Association for the Advancement of Science (AAAS)
2020
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/1721.1/124802 |
| _version_ | 1826217935138455552 |
|---|---|
| author | Ngo, Lizzie Samson, Leona D. Engelward, Bevin P. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Ngo, Lizzie Samson, Leona D. Engelward, Bevin P. |
| author_sort | Ngo, Lizzie |
| collection | MIT |
| description | Certain Escherichia coli strains residing in the human gut produce colibactin, a small-molecule genotoxin implicated in colorectal cancer pathogenesis. However, colibactin’s chemical structure and the molecular mechanism underlying its genotoxic effects have remained unknown for more than a decade. Here we combine an untargeted DNA adductomics approach with chemical synthesis to identify and characterize a covalent DNA modification from human cell lines treated with colibactin-producing E. coli. Our data establish that colibactin alkylates DNA with an unusual electrophilic cyclopropane. We show that this metabolite is formed in mice colonized by colibactin-producing E. coli and is likely derived from an initially formed, unstable colibactin-DNA adduct. Our findings reveal a potential biomarker for colibactin exposure and provide mechanistic insights into how a gut microbe may contribute to colorectal carcinogenesis. |
| first_indexed | 2024-09-23T17:11:23Z |
| format | Article |
| id | mit-1721.1/124802 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T17:11:23Z |
| publishDate | 2020 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1248022022-10-03T11:02:11Z The human gut bacterial genotoxin colibactin alkylates DNA Ngo, Lizzie Samson, Leona D. Engelward, Bevin P. Massachusetts Institute of Technology. Department of Biological Engineering Multidisciplinary Certain Escherichia coli strains residing in the human gut produce colibactin, a small-molecule genotoxin implicated in colorectal cancer pathogenesis. However, colibactin’s chemical structure and the molecular mechanism underlying its genotoxic effects have remained unknown for more than a decade. Here we combine an untargeted DNA adductomics approach with chemical synthesis to identify and characterize a covalent DNA modification from human cell lines treated with colibactin-producing E. coli. Our data establish that colibactin alkylates DNA with an unusual electrophilic cyclopropane. We show that this metabolite is formed in mice colonized by colibactin-producing E. coli and is likely derived from an initially formed, unstable colibactin-DNA adduct. Our findings reveal a potential biomarker for colibactin exposure and provide mechanistic insights into how a gut microbe may contribute to colorectal carcinogenesis. National Institutes of Health (U.S.) (Grant R01 ES022872) National Institute of Environmental Health Sciences (Grant R44 ES024698) National Institute of Environmental Health Sciences (Grant P30 ES002109) National Cancer Institute (U.S.) (Cancer Center Support Grant CA-77598) 2020-04-22T16:43:38Z 2020-04-22T16:43:38Z 2019-02-14 2020-03-05T18:14:15Z Article http://purl.org/eprint/type/JournalArticle 0036-8075 1095-9203 https://hdl.handle.net/1721.1/124802 Wilson, Matthew R. et al. “The human gut bacterial genotoxin colibactin alkylates DNA.” Science 363 (2019): 6428 © 2019 The Author(s) en 10.1126/science.aar7785 Science Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Multidisciplinary Ngo, Lizzie Samson, Leona D. Engelward, Bevin P. The human gut bacterial genotoxin colibactin alkylates DNA |
| title | The human gut bacterial genotoxin colibactin alkylates DNA |
| title_full | The human gut bacterial genotoxin colibactin alkylates DNA |
| title_fullStr | The human gut bacterial genotoxin colibactin alkylates DNA |
| title_full_unstemmed | The human gut bacterial genotoxin colibactin alkylates DNA |
| title_short | The human gut bacterial genotoxin colibactin alkylates DNA |
| title_sort | human gut bacterial genotoxin colibactin alkylates dna |
| topic | Multidisciplinary |
| url | https://hdl.handle.net/1721.1/124802 |
| work_keys_str_mv | AT ngolizzie thehumangutbacterialgenotoxincolibactinalkylatesdna AT samsonleonad thehumangutbacterialgenotoxincolibactinalkylatesdna AT engelwardbevinp thehumangutbacterialgenotoxincolibactinalkylatesdna AT ngolizzie humangutbacterialgenotoxincolibactinalkylatesdna AT samsonleonad humangutbacterialgenotoxincolibactinalkylatesdna AT engelwardbevinp humangutbacterialgenotoxincolibactinalkylatesdna |