The human gut bacterial genotoxin colibactin alkylates DNA-Reference-Cited by-同舟云学术

The human gut bacterial genotoxin colibactin alkylates DNA

Published:2019-02-15 Issue:6428 Volume:363 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Wilson Matthew R.¹^ORCID,Jiang Yindi¹^ORCID,Villalta Peter W.²^ORCID,Stornetta Alessia²^ORCID,Boudreau Paul D.¹^ORCID,Carrá Andrea²^ORCID,Brennan Caitlin A.³^ORCID,Chun Eunyoung³^ORCID,Ngo Lizzie⁴^ORCID,Samson Leona D.⁴^ORCID,Engelward Bevin P.⁴^ORCID,Garrett Wendy S.³⁵⁶^ORCID,Balbo Silvia²^ORCID,Balskus Emily P.¹^ORCID

Affiliation:

1. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.

2. Masonic Cancer Center, University of Minnesota, 2231 Sixth Street Southeast, Minneapolis, MN 55455, USA.

3. Department of Immunology and Infectious Diseases and Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.

4. Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.

5. Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

6. Department of Medical Oncology, Dana-Farber Institute, Boston, MA 02115, USA.

Abstract

Bacterial warhead targets DNA The bacterial toxin colibactin causes double-stranded DNA breaks and is associated with the occurrence of bacterially induced colorectal cancer in humans. However, isolation of colibactin is difficult, and its mode of action is poorly understood. Wilson et al. studied Escherichia coli that contain the biosynthetic gene island called pks , which is associated with colibactin production (see the Perspective by Bleich and Arthur). They identified the DNA adducts that resulted from incubating pks + E. coli in human cells. To overcome the lack of colibactin for direct analysis, mimics of the pks product were synthesized. From the resulting synthetic adenine-colibactin adducts, it became evident that alkylation via a cyclopropane “warhead” breaks the DNA strands. Similar DNA adducts were then identified in the gut epithelia of mice infected with pks + E. coli. Science , this issue p. eaar7785 ; see also p. 689

Funder

David and Lucile Packard Foundation

American Cancer Society

National Cancer Institute

Damon Runyon Cancer Research Foundation

National Institute of Environmental Health Sciences

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference41 articles.

1. The Human Intestinal Microbiome in Health and Disease