New publication in Nature Medicine
Bacteria leave signature in colon cancer cells
A role of colibactin-producing E. coli in carcinogenesis
Starting from the hypothesis that DNA damage by the colibactin genotoxin in the human genome might not be random, the authors determined the locations of double-strand breaks generated after the infection of human cells with colibactin-positive E. coli. They found a strong enrichment of breaks at a distinct sequence motif that exhibited extreme structural features. Computer modelling indicated that the target adenine:thymidine-rich motif is located in a particularly narrow groove area in the DNA, nicely fitting binding by colibactin (see Figure). When the researchers explored whether this colibactin damage motif (CDM) was mutated in human cancers, they found a strong enrichment of CDM-associated mutations in a subgroup of human colorectal cancers. Moreover, the position where colibactin caused the damage in the target DNA, i.e. where it reacted with the two adenines, corresponded exactly with the location of the mutations in the colon cancer genomes. Obviously, in the course of repairing the affected DNA, the human cell happens to make occasional mistakes by incorporating a mismatched nucleotide. Interestingly, the researchers noted that this faulty rescue has a slight bias towards the incorporation of a guanine or a cytosine in the respective DNA strands. These observations point to a highly specific mutational signature, termed SBSA, which has been recently noted in another study to be present in seemingly healthy intestinal tissue. The researchers also asked whether the mutations caused by colibactin have an impact on carcinogenesis. In colon cancer, mutations in the tumor suppressor APC usually occur first as they tend to confer independence of certain growth factors. Interestingly, other bacteria were also shown to carry the genomic island responsible for colibactin synthesis, or produce other genotoxins that cause cancer-promoting mutagenesis. This opens new avenues of research into the interaction of the microbial genotoxins and epithelial cells and their role in carcinogenesis.
The study, initially presented in the preprint repository of bioRxiv last October and now published in Nature Medicine, was performed in collaboration with scientists at the University of Helsinki, the Karolinska Institute Stockholm and the Institute for Research in Biomedicine Barcelona.