Compaction and Segregation of Sister Chromatids by Loop-Extruding Enzymes

Abstract

During cell division, two copies of each chromosome are segregated from each other and compacted more than hundred-fold into the canonical X-shaped structures. According to earlier microscopic observations and the recent Hi-C study, mitotic chromosomes are compacted into arrays of consecutive loops of ∼100 kb. Mechanisms leading to formation of such loop arrays are largely unknown. It has been proposed that SMC complexes involved in chromosome condensation can extrude chromatin loops, leading to formation of arrays of consecutive loops. Here, we use computer simulations to test whether the proposed loop-extruding activity of SMCs could compact and segregate sister chromatids. First, we model the system of loop-extruding SMCs on a chromatin fiber and show that it self-organizes into an array of consecutive dynamic loops. The structure of this array depends on microscopic properties of loop-extruding SMCs and can be predicted with a simple analytical model. Second, we model the process of loop extrusion in 3D and show that, coupled with the topo II strand-passing activity, it leads to robust compaction and segregation of sister chromatids. We show that loop-extruding proteins transform individual chromatids into bottle-brush structures consistent with the microscopic observations and Hi-C-based models. These bottle-brush chromatids repel each other allowing topo II to disentangle them. This mechanism of chromosomal condensation and segregation does not require additional proteins or specific DNA markup and is robust against variations in SMC number and properties.