Building bridges between chromosomes: novel insights into the abscission checkpoint

Abstract

In the presence of chromatin bridges, mammalian cells delay completion of cytokinesis (abscission) to prevent chromatin breakage or tetraploidization by regression of the cleavage furrow. This abscission delay is called "the abscission checkpoint" and is dependent on Aurora B kinase. Furthermore, cells stabilize the narrow cytoplasmic canal between the two daughter cells until the DNA bridges are resolved. Impaired abscission checkpoint signaling or unstable intercellular canals can lead to accumulation of DNA damage, aneuploidy, or generation of polyploid cells which are associated with tumourigenesis. However, the molecular mechanisms involved have only recently started to emerge. In this review, we focus on the molecular pathways of the abscission checkpoint and describe newly identified triggers, Aurora B-regulators and effector proteins in abscission checkpoint signaling. We also describe mechanisms that control intercellular bridge stabilization, DNA bridge resolution, or abscission checkpoint silencing upon satisfaction, and discuss how abscission checkpoint proteins can be targeted to potentially improve cancer therapy.

Keywords: CPC; Chk1; Chmp4; ESCRT; Midbody; Src.

Fig. 1

For completion of cytokinesis, plasma membrane cutting is coordinated with reorganization of the cytoskeleton inside the intercellular canal. Molecular pathways that lead to membrane cutting by ESCRT-III protein filaments, depolymerization of F-actin, and microtubule severing are indicated. The horizontal dashed line marks the formation of the secondary ingression site

Fig. 2

Active Aurora B kinase translocates inside the Flemming body to implement the abscission checkpoint in late cytokinesis. a Midbody cartoon. b Localization of Aurora B to the midbody arms and inside the Flemming body in relatively early or late midbodies. See text for details

Fig. 3

Abscission checkpoint pathways in higher eukaryotic cells. a Abscission checkpoint signaling in normal mitosis, in the presence of chromatin bridges, or in response to nuclear pore defects. The proposed “central circuit” of the abscission checkpoint is shown in blue background. The double-headed arrow indicates that ULK3 acts both upstream and downstream of Chmp4c. b, c Abscission checkpoint signaling in response to relatively mild DNA replication stress (b), or high bridge-tension (c). See text for details. p phosphorylation. Unknown molecular events are indicated by question marks. Arrows indicate absolute requirements

Fig. 4

Stabilization of chromatin bridges and intercellular canals in late cytokinesis. a Molecular mechanism of actin patch formation. b Proposed mechanisms that promote anchoring of the plasma membrane (PM) to the cell cortex. p phosphorylation. Unknown molecular events are indicated by question marks. Arrows indicate absolute requirements

Fig. 5

Potential outcomes of abscission checkpoint delay in cells with chromatin bridges. In checkpoint-proficient cells, chromatin bridges can be resolved without permanent DNA damage (I), lead to DNA fragmentation (II), or generation of tetraploid cells (III). NERDI, nuclear envelope rupture during interphase. PM, plasma membrane

Fig. 6

Silencing the abscission checkpoint in normal mitosis. a Upon checkpoint satisfaction, PP1 counteracts the Aurora B-mediated Chmp4c-S210 phosphorylation to switch the checkpoint off. Also b, PKCε phosphorylates Aurora B-S227 to promote phosphorylation of Borealin, proper Chmp4c localization to the midbody, and abscission. Red lines, abscission checkpoint signaling. Green lines, abscission checkpoint silencing pathways. p phosphorylation. Arrows indicate abslolute requirements