An inter-disciplinary team of researchers form the Hong Kong University of Science and Technology (HKUST) unravel how a toxin released by E.coli is linked to colorectal cancer through a synthetic biology approach.
Escherichia coli (E.coli), a human gut bacterium known to assist in food digestion and regulation of our immune system, also contains toxins that could halt cell cycles and eventually cause cell death. Scientists have long known that colibactin – a genotoxin produced by E.coli can induce DNA mutations in eukaryotic cells and increase the of colorectal cancer in humans. However, the cancer-causing mechanism of colibactin had been a mystery as reconstructing colibactin metabolites is extremely tedious due to the instability of the compound, low titre and complexity of its biosynthetic pathway.
The research team led by Professor Qian Peiyuan, David von Hansemann Professor of Science and Chair Professor of HKUST’s Department of Ocean Science and Division of Life Science, discovered the missing link using a novel biosynthetic method. The team also succeeded in cloning the colibactin gene cluster and found a way to mass produce the genes for testing and validation. After many assays of various sets of colibactin precursors, the team eventually identified colibactin-645 as the cause for DNA mutation and unravelled the colibactin metabolite 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.
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. [APBN]