Mitotic chromosome alignment ensures mitotic fidelity by promoting interchromosomal compaction during anaphase

Abstract

Chromosome alignment at the equator of the mitotic spindle is a highly conserved step during cell division; however, its importance to genomic stability and cellular fitness is not understood. Normal mammalian somatic cells lacking KIF18A function complete cell division without aligning chromosomes. These alignment-deficient cells display normal chromosome copy numbers in vitro and in vivo, suggesting that chromosome alignment is largely dispensable for maintenance of euploidy. However, we find that loss of chromosome alignment leads to interchromosomal compaction defects during anaphase, abnormal organization of chromosomes into a single nucleus at mitotic exit, and the formation of micronuclei in vitro and in vivo. These defects slow cell proliferation and are associated with impaired postnatal growth and survival in mice. Our studies support a model in which the alignment of mitotic chromosomes promotes proper organization of chromosomes into a single nucleus and continued proliferation by ensuring that chromosomes segregate as a compact mass during anaphase.

The coordination of nuclear envelope assembly and chromosome segregation in metazoans

“…First, the ensemble segregation of anaphase chromosomes is facilitated by a complex signaling mechanism called the spindle assembly checkpoint, which ensures correct microtubule attachments to mitotic chromosomes [46]. In part through the concerted action of motor proteins [14,47,48], correctly attached chromosomes are kept in close physical proximity as they move toward the spindle poles during anaphase. This clustering of chromosomes is an important physical characteristic of mitosis that promotes the formation of a single nucleus.…”

“…These chromosomes either join the main mass of chromosomes or wind up close enough to be incorporated together into one nucleus (Figure 3 (a)). Therefore, the observation that many lagging chromosomes are incorporated into a single daughter nucleus [47] can simply be explained by timing; it does not, in and of itself, imply that the reintegration is actively promoted by an Aurora B-mediated surveillance/checkpoint mechanism.…”

“…Therefore, variable position of lagging chromosomes within the mitotic spindle may explain the partial penetrance of the NPC depletion observed on micronuclei [21][22][23]. Spindle geometry and ER organization vary greatly between cell types [81,128,129], and these variations likely contribute to differences in micronucleation frequencies and the extent of their defects [47,94].…”

Organelle size scaling over embryonic development

“…In zebrafish, the protein brambleberry ensures that these karyomeres fuse into a single nucleus (Abrams et al, 2012). In C. elegans embryos, a paired nuclei phenotype results when Polo-like kinase PLK-1 or the lipin activator CNEP-1 is inhibited (Bahmanyar et al, 2014;Rahman et al, 2015), bilobed nuclei form in yeast secretion mutants (Walters et al, 2019), and in human cells BAF and KIF18A are important for the formation of a single nucleus after mitosis (Fonseca et al, 2019;Samwer et al, 2017). Failure of these mechanisms can have dire consequences, for instance many cancers exhibit micronuclei in which massive genomic rearrangements called chromothripsis can drive cancer progression (Crasta et al, 2012;Hatch, Fischer, Deerinck, & Hetzer, 2013;C.…”

Optogenetic control of PRC1 reveals that bridging fibers promote chromosome alignment by overlap length-dependent forces

“…Pre-anaphase chromosome movements culminate with chromosome alignment at the spindle equator, a distinctive feature of mitosis important for the synchronous anaphase poleward movement of chromatids and proper telophase nuclear reformation (Fonseca et al, 2019;Maiato et al, 2017). Chromosome congression to the metaphase plate, a process of directed chromosome movement from the polar regions towards the spindle equator, has been explored extensively (Barisic et al, 2014;Cai et al, 2009;Kapoor et al, 2006;Maiato et al, 2017).…”