Revealing A-T and G-C Hoogsteen base pairs in stressed protein-bound duplex DNA

Watson–Crick base pairs (bps) are the fundamental unit of genetic information and the building blocks of the DNA double helix. However, A-T and G-C can also form alternative ‘Hoogsteen’ bps, expanding the functional complexity of DNA. We developed ‘Hoog-finder’, which uses structural fingerprints to rapidly screen Hoogsteen bps, which may have been mismodeled as Watson–Crick in crystal structures of protein–DNA complexes. We uncovered 17 Hoogsteen bps, 7 of which were in complex with 6 proteins never before shown to bind Hoogsteen bps. The Hoogsteen bps occur near mismatches, nicks and lesions and some appear to participate in recognition and damage repair. Our results suggest a potentially broad role for Hoogsteen bps in stressed regions of the genome and call for a community-wide effort to identify these bps in current and future crystal structures of DNA and its complexes.