Shaping mitotic chromosomes: From classical concepts to molecular mechanisms

Abstract

How eukaryotic genomes are packaged into compact cylindrical chromosomes in preparation for cell divisions has remained one of the major unsolved questions of cell biology. Novel approaches to study the topology of DNA helices inside the nuclei of intact cells, paired with computational modeling and precise biomechanical measurements of isolated chromosomes, have advanced our understanding of mitotic chromosome architecture. In this Review Essay, we discuss - in light of these recent insights - the role of chromatin architecture and the functions and possible mechanisms of SMC protein complexes and other molecular machines in the formation of mitotic chromosomes. Based on the information available, we propose a stepwise model of mitotic chromosome condensation that envisions the sequential generation of intra-chromosomal linkages by condensin complexes in the context of cohesin-mediated inter-chromosomal linkages, assisted by topoisomerase II. The described scenario results in rod-shaped metaphase chromosomes ready for their segregation to the cell poles.

Keywords: SMC complex; chromosome condensation; chromosome segregation; cohesin; condensin; mitosis; topoisomerase II.

Figure 1

Levels of chromosome organization. A: Cartoon models of nucleosomes composed of DNA (dark gray tube) wrapped around an octamer of histones H2A, H2B, H3, and H4 (light gray cylinder) and of one-start (solenoid) and two-start (zigzag) 30 nm fibers. B: Proposed steps in folding an 11 nm nucleosome fiber into a mitotic chromosome by formation of loops of 80–120 kb in size, followed by compression along the longitudinal chromosome axis and reduction in chromosome diameter by lateral compression.

Figure 2

A three-step linkage model for the condensation of a mammalian chromosome. Sister chromatids (light and dark gray lines) held together by their entrapment within cohesin rings (yellow) are organized into linear arrays of loops by condensin II (purple). Loop sizes might be limited to 80–120 kb by restricted action of condensin II within the region between two cohesin binding sites. Release of the bulk of cohesin from chromosome arms by the prophase pathway allows the generation of linkages between different loops by condensin II, resulting in a linear compression along the longitudinal chromosome axis. Topo IIα (green) might help in this process by catalyzing intra-chromatid strand passage. Binding of condensin I (red) after NEBD results in lateral compression by fastening loops that protrude from the chromosome and thereby assists in removal of residual arm cohesion and directs inter-chromatid decatenation by topo IIα.