Histone octamers (hos) and DNA topoisomerase I contribute, along with other proteins, to the higher order structure of chromatin. Here we report on the similar topological requirements of these two protein model systems for their interaction with DNA. Both histone octamers and topoisomerase I positively and consistently respond to DNA supercoiling and curvature, and to the spatial accessibility of the preferential interaction sites. These findings (1) point to the relevance of the topology‐related DNA conformation in protein interactions and define the (...) particular role of the helically phased rotational information; and (2) help to solve the apparent paradoxical behaviour of ubiquitous and abundant proteins that interact with defined DNA sites in spite of the lack of clear sequence consensuses. Considering firstly, that the interactions with DNA of both DNA topoisomerase I and histone octamers are topology‐sensitive and that upon their interaction the DNA conformation is modified; and secondly, that similar behaviours have also been reported for DNA topoisomerase II and histone H1, a topology‐based functional correlation among all these determinants of the higher order structure of chromatin is here suggested. (shrink)