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

Abstract 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 seventeen Hoogsteen bps, seven of which were in complex with six 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.