The human gut bacterial genotoxin colibactin alkylates DNA

被引：483

作者：

Wilson, Matthew R. ^{[1
,8
]}

Jiang, Yindi ^{[1
]}

Villalta, Peter W. ^{[2
]}

Stornetta, Alessia ^{[2
]}

Boudreau, Paul D. ^{[1
]}

Carra, Andrea ^{[2
]}

Brennan, Caitlin A. ^{[3
,4
]}

Chun, Eunyoung ^{[3
,4
]}

Ngo, Lizzie ^{[5
]}

Samson, Leona D. ^{[5
]}

Engelward, Bevin P. ^{[5
]}

Garrett, Wendy S. ^{[3
,4
,6
,7
]}

Balbo, Silvia ^{[2
]}

Balskus, Emily P. ^{[1
]}

机构：

[1] Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA

[2] Univ Minnesota, Masonic Canc Ctr, 2231 Sixth St Southeast, Minneapolis, MN 55455 USA

[3] Harvard T H Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA

[4] Harvard T H Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA

[5] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[6] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[7] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[8] Vertex Pharmaceut, 50 Northern Ave, Boston, MA 02210 USA

来源：

SCIENCE | 2019年 / 363卷 / 6428期

基金：

美国国家卫生研究院;

关键词：

IN-VIVO; DAMAGE; BIOSYNTHESIS; ADDUCTS; INSTABILITY; MECHANISM; REPAIR;

D O I：

10.1126/science.aar7785

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：709 / +

页数：100

共 41 条

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