Relocation of the Chromosomal Passenger Complex Prevents Mitotic Checkpoint Engagement at Anaphase

Abstract

The mitotic checkpoint monitors the attachment of kinetochores to microtubules and delays anaphase onset until all sister kinetochores have become attached to opposite poles [1, 2]. Correct bipolar attachment leads to kinetochore deformation and tension and satisfies the checkpoint [3-6]. What prevents mitotic checkpoint reactivation when sister centromeres are split and tension is lost at anaphase onset? Aurora B kinase, the catalytic subunit of the chromosomal passenger protein complex (CPC) [7], acts as a sensor at inner centromeres for the status of attachment [5, 8]. Phosphorylation of Aurora B targets at erroneously attached kinetochores elicits the correction of these attachments and the activation of the mitotic checkpoint. At anaphase, the CPC leaves the centromeres and relocates to the spindle midzone [7]. This iconic translocation might prevent the checkpoint from reengaging after anaphase onset. To test this hypothesis, we experimentally retained Aurora B and the CPC at the centromere throughout anaphase in human cells. Preventing CPC translocation caused the untimely recruitment of mitotic checkpoint proteins to kinetochores at anaphase in an Aurora B kinase activity-dependent manner. Our results suggest that the relocalization of the CPC, an evolutionarily conserved event in eukaryotes, is a key mechanism that incapacitates the mitotic checkpoint at anaphase.

Ewing sarcoma EWS protein regulates midzone formation by recruiting Aurora B kinase to the midzone

“…37 A high level of Aurora B protein expression can lead to a failure in relocation. AURORA B was among numerous cell cycle regulators that have been identified as EWS/FLI1 target genes, and AURORA B mRNA is upregulated in Ewing sarcoma cells.…”

Inefficient degradation of cyclin B1 re-activates the spindle checkpoint right after sister chromatid disjunction

“…10,14,15 Here, we measured the translocation of a fluorescently-tagged version of the Aurora B-binding chromosomal passenger protein INCENP. In control cells, all INCENP-EGFP translocated from the DNA toward the midzone 10-15 min after sister chromatid separation (Fig.…”

“…The problem appears to be avoided by the timely inactivation of Cdk1 prior to anaphase, in metaphase. [10][11][12][13][14][15] It is unknown at the moment whether the anaphase problem could occur naturally, or may contribute to aneuploidy in cases when Cdk1 regulatory factors are abnormally expressed. How inactivation of Cdk1 prevents the anaphase problem is also still largely unclear.…”

Tension at EMBO's Aneuploidy Workshop

“…petronczki's lab anchored aurora B to centro meres, thereby preventing its relo calization at anaphase onset. they found that this recruits a subset of Sac proteins to anaphase kinetochores (Vázqueznovelle & petronczki, 2010). taken together, these results suggest that cpc relocation removes the tension sensor from kinetochores to inactivate the checkpoint, thereby prevent ing its reengagement when tension is lost in anaphase.…”