| Popis: |
SUMMARYThe topological state of chromosomes is an important factor controlling their mechanical properties, dynamics and function. Recent work has shown that interphase chromosomes are largely free of entanglements. How cycling cells establish this state from a dense mitotic chromosome and maintain it through interphase in the presence of Topoisomerase II activity remains mysterious. Using multi-contact 3C, Hi-C, and polymer simulations, we find that mitotic chromosomes are intrachromosomally entangled, while interphase chromosomes are not, pointing to cell cycle-dependent control of chromosome topology. The majority of mitotic entanglements are removed during anaphase/telophase, with most of the remaining ones removed during early G1, in a process that requires Topoisomerase II. Polymer simulations show that swelling and decondensation of mitotic chromosomes during mitotic exit produce entropic forces that bias Topoisomerase II activity towards decatenation of condensin loops. This is followed by prevention of formation of new entanglements by lower Topoisomerase II activity in G1, and, in heterochromatic B compartments, by interplay between cohesin and Topoisomerase II. Our results show how cells control chromosome topology during mitotic exit and G1 employing both biophysical and molecular mechanisms to modulate Topoisomerase II activity and directionality. |
