Maximal chromosome compaction occurs by axial shortening in anaphase and depends on Aurora kinase

Abstract

Eukaryotic cells must first compact their chromosomes before faithfully segregating them during cell division. Failure to do so can lead to segregation defects with pathological consequences, such as aneuploidy and cancer. Duplicated interphase chromosomes are, therefore, reorganized into tight rods before being separated and directed to the newly forming daughter cells. This vital reorganization of chromatin remains poorly understood. To address the dynamics of mitotic condensation of single chromosomes in intact cells, we developed quantitative assays based on confocal time-lapse microscopy of live mammalian cells stably expressing fluorescently tagged core histones. Surprisingly, maximal compaction was not reached in metaphase, but in late anaphase, after sister chromatid segregation. We show that anaphase compaction proceeds by a mechanism of axial shortening of the chromatid arms from telomere to centromere. Chromatid axial shortening was not affected in condensin-depleted cells, but depended instead on dynamic microtubules and Aurora kinase. Acute perturbation of this compaction resulted in failure to rescue segregation defects and in multilobed daughter nuclei, suggesting functions in chromosome segregation and nuclear architecture.

SPOC1: a novel PHD-containing protein modulating chromatin structure and mitotic chromosome condensation

“…3C,D), the two stages of the mitotic cell cycle where chromosome condensation occurs, and since defects in mitotic chromosome condensation have been previously reported to lead to the pleiotropic mitotic defects (Cimini et al, 2003;Inoue et al, 2008;Mora-Bermudez et al, 2007;Nasmyth, 2002; Yong-Gonzalez et al, 2007) that we have observed Fig. 3.…”

“…Reducing SPOC1 protein levels resulted in various mitotic defects such as hypocondensed mitotic chromosomes, misalignment and segregation defects. Similar mitotic defects have been previously described after the disruption of other important factors involved in mitotic chromosome condensation (Cimini et al, 2003;Nasmyth, 2002;Somma et al, 2003) such as, components of the condensin complex (Yong-Gonzalez et al, 2007), chromokinesins (Mazumdar and Misteli, 2005;Mazumdar et al, 2004) topoisomerase IIα (Dawlaty et al, 2008;Downes et al, 1991), aurora kinase (Mora-Bermudez et al, 2007) and HP1α (Inoue et al, 2008). This can be explained by the fact that the failure of a mitotic cell to properly condense it chromosomes can result in unresolved sister chromatids, which can preclude successful metaphase alignment, often resulting in mitotic delays owing to activated checkpoints and ultimately leading to various segregation defects, such as lagging chromosomes, chromosome bridges and aneuploidy or polyploidy (Arlot-Bonnemains et al, 2001;Cortes and Pastor, 2003;Fu et al, 2007;Giet and Glover, 2001;Hodges et al, 2005;Storchova et al, 2006).…”

The life cycle of the metazoan nuclear envelope

“…Interestingly, maximal chromatin compaction is not reached in metaphase but in late anaphase, after sister chromatid segregation [45]. The chromokinesin kinesin-like DNA binding protein (Kid) has recently been show to be required for the formation of a compact chromosome cluster during anaphase and the proper enclosure of the segregated chromosomes into a single nucleus [46].…”

Cell cycle control of spindle elongation

“…Although it is generally believed that maximal chromosome condensation is achieved in metaphase when chromosomes line up on the metaphase plate, this view has been challenged recently. 17 Live-cell imaging of HeLa cells reveals that maximal compaction actually occurs as cells progress through anaphase B, 17 emphasizing the importance of condensation in chromosome segregation. Thus, chromosome condensation in combination with anaphase A is crucial for faithful chromosome segregation in higher eukaryotes.…”

“…[10][11][12][13] Finally, as discussed below, a significant assistance to chromosome segregation in higher eukaryotes comes from condensation and compaction of mitotic chromosomes. [14][15][16][17] …”