HKUST researchers unlock cancer-causing mechanism of E. coli toxin with synthetic biology approach

September 17, 2019

While human gut microbes like E. coli help digest food and regulate our immune system, they also contain toxins that could arrest cell cycle and eventually cause cell death. Scientists have long known that colibactin - a genotoxin produced by E. coli, can induce DNA double-strand breaks in eukaryotic cells and increase the risk of colorectal cancer in human. However, how colibactin causes DNA damage had remained a mystery as reconstructing colibactin metabolites is extremely difficult due to the compound's instability, low titer and complexity of its biosynthetic pathway.

Now, a research team led by Prof. Qian Peiyuan, Chair Professor of HKUST's Department of Ocean Science and Division of Life Science, have unearthed the missing link using a novel biosynthetic method. The team not only succeeded in cloning the colibactin gene cluster, but also found a way to mass produce the genes for testing and validation. After repeated assays of various sets of colibactin precursors, the team eventually identified colibactin-645 as the culprit of the DNA double-strand breaks, and uncovered colibactin metabolite's biosynthetic pathway as well as its mechanism of causing DNA damage.

Prof. Qian said, "Although a few colibactin metabolites have been reported to damage DNA via DNA crosslinking activity, the genotoxic colibactin that possesses DNA double-strands directly is yet-to-be-identified. Our research has confirmed colibactin-645 exerts direct DNA double-strand breaks, that unearthed the missing link that correlates colibactin to its health effects on human beings."

LI Zhongrui, a researcher of the team, said the restructuring of colibactin's molecular scaffold provides a model for designing and synthesizing potent DNA cleaving agents - such as synthetic restriction "enzymes" or chemotherapeutic agents.
-end-
In collaboration with University of California at Berkeley and Scripps Institution of Oceanography of University of California, San Diego, the research findings were recently published in the prestigious scientific journal Nature Chemistry and the early findings on colibactin were published in another scientific journal Nature Chemical Biology.

*According to the statistics of World Cancer Research Fund 2018: https://www.wcrf.org/dietandcancer/cancer-trends/colorectal-cancer-statistics

Hong Kong University of Science and Technology

Related Colorectal Cancer Articles from Brightsurf:

Colorectal cancer treatment: the winning combinations
Chemotherapy has distressing side effects for patients and increases the risk of developing resistance to the treatment.

A new model to predict survival in colorectal cancer
This signature could be useful in clinical practice, especially for colorectal cancer diagnosis and therapy.

Roadmap to reducing colorectal cancer deaths
The American Gastroenterological Association has outlined a strategy to increase the number of people screened via tests that are more convenient, accurate and less expensive and tailored to people's individual cancer risks.

Study provides new insight on colorectal cancer growth
A new study by researchers at the University of Kentucky identifies a novel function of the enzyme spermine synthase to facilitate colorectal cancer growth.

Researchers ID target for colorectal cancer immunotherapy
Researchers at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center have identified a target for colorectal cancer immunotherapy.

Colorectal cancer partner-in-crime identified
A protein that helps colorectal cancer cells spread to other parts of the body could be an effective treatment target.

Cancer cell reversion may offer a new approach to colorectal cancer treatment
A novel approach to reverse the progression of healthy cells to malignant ones may offer a more effective way to eradicate colorectal cancer cells with far fewer side effects, according to a KAIST research team based in South Korea.

A novel pathway to target colorectal cancer
Survival rates for patients with late-stage colorectal cancer are dismal, and new therapeutic strategies are needed to improve outcomes.

Colorectal cancer rates in Canada
The incidence of colorectal cancer among younger adults increased in recent years in this analysis of data from Canadian national cancer registries that included about 688,000 new colorectal cancers diagnosed over more than 40 years.

Cancer drugs promote stem cell properties of colorectal cancer
Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the Mannheim University Medical Center have now discovered that a certain group of cancer drugs (MEK Inhibitors) activates the cancer-promoting Wnt signalling pathway in colorectal cancer cells.

Read More: Colorectal Cancer News and Colorectal Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.