Thermodynamics and kinetics of TopoII action: A consensus on T-segment curvature selection? Comment on "Disentangling DNA Molecules" by Alexander Vologodskii.

In his Physics of Life review, Vologodskii [1] advocates for a “merging” of the hooked-juxtaposition [2] and bendangle (bent G segment) [3,4] models of disentangling by type II topoisomerases (topoIIs). His review is significant because it signals an emerging consensus, at least among theoreticians, that topoIIs perform T-segment selection [5]. As a researcher of DNA topology who has made important contributions, and particularly as a long-time proponent of active bending of the G-segment by topoII with no curvature selection of the T-segment [4], Vologodskii’s change of opinion is compelling. Although structural data exist only for a topoII-bound curved G-segment [6], indirect evidence that narrows theoretical choices to a hooked-juxtaposition-like T-segment selection mechanism has been accumulating. For instance, a recent single-molecule measurement ruled out an alternative kinetic proofreading model [7]. Moreover, an atomic force microscopy study showed that G-segment bending is not the sole determinant of a topoII’s disentangling power [8]. Perhaps most notably, direct evidence has been obtained for T-segment selection, though the property being selected remains to be elucidated [9]. In fact, theoretical support for T-segment selection, especially with regard to topoII’s Lk narrowing action, is more preponderant than that presented by Vologodskii, who stated that analysis of 〈( Lk)2〉 reduction “has been performed for only one model of the phenomenon” [1]. But there are two other theoretical studies of Lk narrowing [5,10]. In particular, using a wormlike DNA model [11] together with an analytical formulation, we have obtained 〈( Lk)2〉 reduction factors RLk ≈ 1.7—1.8 for DNA circle size 3.5 kb by segment passage at hook-like juxtapositions. The computed RLk values are in good agreement with experiment [5,9,12]. A broader view of the predicted disentangling