The microbial toxin colibactin has just the right shape to snuggle up to DNA — but its embrace is unfortunately more cancerous than cozy.
Colibactin is produced by bacteria in the gut and causes mutations implicated in colon cancer. It bears chemical motifs so good at damaging DNA that scientists call them “warheads.” And now, a close look at colibactin as it reacts with DNA has revealed how it seeks and destroys: Its structure grants it a pesky proclivity to target particular stretches of DNA, researchers report December 4 in Science.
The discovery forges a strong link between colibactin and specific “fingerprints” of mutation observed in colon cancer. Scientists could eventually use those fingerprints to develop tests for colibactin exposure and arm doctors with better tools for evaluating cancer risk.
Most gut bacteria are beneficial or neutral, but some, including some strains of Escherichia coli, produce toxins like colibactin and are downright destructive. Since colibactin was discovered in 2006, evidence that it contributes to colon cancer — a disease that will strike about 1 in 25 people in the United States in their lifetimes — has been piling up.
One of the strongest hints comes from the unique patterns of mutations carried by human colon cancers. Colibactin doesn’t damage DNA willy-nilly. It inflicts specific mutations within particular short “words,” or sequences, written in DNA’s four-letter chemical alphabet. Those mutations show up in the genetic fingerprint of 5 to 20 percent of colon cancers. E. coli carrying the genes required to build colibactin are found more often in colon cancer patients than in healthy people. And experiments have linked colibactin exposure to DNA damage and cellular aging in human cells and tumor formation in mice.
But despite all this promising evidence implicating colibactin in cancer, the molecule’s structure — an explanation for how it produces its signature mutations — proved elusive.
