Abstract
The abscission checkpoint contributes to the fidelity of chromosome segregation by delaying completion of cytokinesis (abscission) when there is chromatin lagging in the intercellular bridge between dividing cells. Although additional triggers of an abscission checkpoint-delay have been described, including nuclear pore defects, replication stress or high intercellular bridge tension, this review will focus only on chromatin bridges. In the presence of such abnormal chromosomal tethers in mammalian cells, the abscission checkpoint requires proper localization and optimal kinase activity of the Chromosomal Passenger Complex (CPC)-catalytic subunit Aurora B at the midbody and culminates in the inhibition of Endosomal Sorting Complex Required for Transport-III (ESCRT-III) components at the abscission site to delay the final cut. Furthermore, cells with an active checkpoint stabilize the narrow cytoplasmic canal that connects the two daughter cells until the chromatin bridges are resolved. Unsuccessful resolution of chromatin bridges in checkpoint-deficient cells or in cells with unstable intercellular canals can lead to chromatin bridge breakage or tetraploidization by regression of the cleavage furrow. In turn, these outcomes can lead to accumulation of DNA damage, chromothripsis, generation of hypermutation clusters and chromosomal instability, which are associated with cancer formation or progression. Recently, many important questions regarding the mechanisms of the abscission checkpoint have been investigated, such as how the presence of chromatin bridges is signaled to the CPC, how Aurora B localization and kinase activity is regulated in late midbodies, the signaling pathways by which Aurora B implements the abscission delay, and how the actin cytoskeleton is remodeled to stabilize intercellular canals with DNA bridges. Here, we review recent progress toward understanding the mechanisms of the abscission checkpoint and its role in guarding genome integrity at the chromosome level, and consider its potential implications for cancer therapy.
Highlights
Introduction published maps and institutional affilTo ensure accurate distribution of the genetic material from the parent to the two daughter cells during cell division, completion of cytokinesis is tightly coordinated with chromosome segregation [1]
The MRN localizes to the midbody where it is required for ataxiatelangiectasia mutated (ATM) activation in cytokinesis with chromatin bridges, but not in normally segregating cells (Figure 2b, green; [81])
It is proposed that the MRN-ATM-checkpoint kinase 2 (Chk2)-INCENP pathway regulates Chromosomal Passenger Complex (CPC)-localization to the midbody through INCENP-serine 91 (S91) phosphorylation, to impose the abscission checkpoint and prevent chromatin breakage in cytokinesis (Figure 2b, green)
Summary
Abscission, the final step of cytokinesis during which the narrow intercellular canal that connects the two daughter cells is cleaved, requires plasma membrane remodeling at the constriction sites as well as reorganization of the cytoskeleton inside the intercellular canal (reviewed in [1,19]). In later stages of cytokinesis, ESCRT-III polymers containing Chmp4b and IST1 form spiral structures with progressively smaller diameters at the secondary ingression site (that will become the abscission site) at approximately 1 μm distance from the midbody (Figure 1; [37,38,39]) This reorganization of ESCRT-III into spirals is thought to promote membrane deformation and scission at the abscission site and requires ESCRTbinding to the ATPase Vps, which promotes remodeling of the ESCRT-III filaments by. In addition to F-actin, cells must clear microtubules at the secondary ingression site before canal cleavage For this purpose, the microtubule-severing AAA ATPase spastin directly interacts with the ESCRT-III component Chmp1b and is recruited to the future abscission site to coordinate membrane cutting with microtubule severing (Figure 1; [50,51]). Localized microtubule buckling and breaking may contribute to microtubule severing at the secondary ingression site [45]
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