Control of the Viscoelasticity of the Genome By Topoisomerase Type II and Anti-Cancer Drugs

Abstract

The mechanical, viscoelastic properties of the genome are important for our understanding of cell division and, indirectly cancer therapy. Topology controlling enzymes (topoisomerase type II) are thought to play an essential role, but so far quantitative measurements of the effect on the viscoelasticity of DNA are lacking. We report experiments showing how double strand passage facilitated by human topo II controls the disentanglement of DNA. For this purpose, we have measured the elastic storage and viscous loss modulus of a model system consisting of bacteriophage DNA in buffer solution using video tracking of the Brownian motion of colloidal probe particles. We found that the viscoelastic response is critically dependent on the formation of entanglements among the DNA molecules with relaxation times on the order of seconds. For the first time we observed that topo II effectively removes these entanglements and converts the system from an elastic gel to a viscous fluid depending on the dissipation of energy through the hydrolysis of ATP. A second aspect of this study is the effect of a generic topo II inhibitor on the viscoelasticity. Topo II inhibitors constitute an important class of anti-cancer drugs, because they impede the division of cancerous cells by forming clamps between DNA segments. We continue interpreting our results in terms of a molecular model, which includes the reaction kinetics and functional mechanism. Our work contributes to the understanding of energy dependent, non-equilibrium dynamics of biomolecules, which is a key feature of life.