School of Physics and Astronomy, University of Edinburgh, Edinburgh, UK.
MRC Human Genetics Unit, Western General Hospital, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
J Cell Biol. 2024 Jan 1;223(1). doi: 10.1083/jcb.202209113. Epub 2023 Nov 17.
Eukaryotic chromosomes compact during mitosis into elongated cylinders-and not the spherical globules expected of self-attracting long flexible polymers. This process is mainly driven by condensin-like proteins. Here, we present Brownian-dynamic simulations involving two types of such proteins with different activities. One, which we refer to as looping condensins, anchors long-lived chromatin loops to create bottlebrush structures. The second, referred to as bridging condensins, forms multivalent bridges between distant parts of these loops. We show that binding of bridging condensins leads to the formation of shorter and stiffer mitotic-like cylinders without requiring any additional energy input. These cylinders have several features matching experimental observations. For instance, the axial condensin backbone breaks up into clusters as found by microscopy, and cylinder elasticity qualitatively matches that seen in chromosome pulling experiments. Additionally, simulating global condensin depletion or local faulty condensin loading gives phenotypes seen experimentally and points to a mechanistic basis for the structure of common fragile sites in mitotic chromosomes.
真核染色体在有丝分裂过程中压缩成长形圆柱体，而不是自我吸引的长柔性聚合物所预期的球形小球体。这个过程主要是由类凝缩蛋白驱动的。在这里，我们提出了涉及两种具有不同活性的这类蛋白的布朗动力学模拟。其中一种，我们称之为环化凝缩蛋白，将长寿命染色质环锚定在一起，形成瓶刷结构。第二种，称为桥接凝缩蛋白，在这些环的远距离部分之间形成多价桥。我们表明，桥接凝缩蛋白的结合导致形成更短和更刚性的有丝分裂样圆柱体，而不需要任何额外的能量输入。这些圆柱体具有与实验观察相匹配的几个特征。例如，显微镜发现，轴向凝缩蛋白骨架会分裂成簇，并且圆柱体的弹性与染色体牵拉实验中观察到的弹性定性匹配。此外，模拟全局凝缩蛋白耗竭或局部有缺陷的凝缩蛋白加载会产生实验中观察到的表型，并为有丝分裂染色体中常见脆性位点的结构提供了一种机制基础。
