Colibactin DNA damage signature indicates causative role in colorectal cancer

Dziubanska Kusibab, P. J.; Berger, H.; Battistini, F.; Bowman, B. A.; Iftekhar, A.; Katainen, R.; Crosetto, N.; Orozco, M.; Aaltonen, L. A.; Meyer, T. F.

doi:10.1101/819854

bioRxiv · 10.1101/819854

Colibactin DNA damage signature indicates causative role in colorectal cancer

Dziubanska Kusibab, P. J.·Berger, H.·Battistini, F.·Bowman, B. A.·Iftekhar, A.·Katainen, R.·Crosetto, N.·Orozco, M.·Aaltonen, L. A.·Meyer, T. F.

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Abstract

Colibactin, a potent genotoxin of Escherichia coli, causes DNA double strand breaks (DSBs) in human cells. We investigated if colibactin creates a particular DNA damage signature in infected cells by identifying DSBs in colon cells after infection with pks+ E.coli. Interestingly, genomic contexts of DSBs were enriched for AT-rich penta-/hexameric sequence motifs, exhibiting a particularly narrow minor groove width and extremely negative electrostatic potential. This corresponded with the binding characteristics of colibactin to double-stranded DNA, as elucidated by docking and molecular dynamics simulations. A survey of somatic mutations at the colibactin target sites of several thousand cancer genomes revealed significant enrichment of the identified motifs in colorectal cancers. Our work provides direct evidence for a role of colibactin in the etiology of human cancer.\n\nOne sentence summaryWe identify a mutational signature of colibactin, which is significantly enriched in human colorectal cancers.

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Dziubanska Kusibab, P. J., Berger, H., Battistini, F., Bowman, B. A., Iftekhar, A., Katainen, R., Crosetto, N., Orozco, M., Aaltonen, L. A., Meyer, T. F.. 2019-10-25. Colibactin DNA damage signature indicates causative role in colorectal cancer. https://doi.org/10.1101/819854

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