An anaphase surveillance mechanism prevents micronuclei formation from frequent chromosome segregation errors

Kinetochore life histories reveal an Aurora-B-dependent error correction mechanism in anaphase

“…Lazy kinetochores persist when Aurora B is inhibited, which increases the rate of micronuclei formation, hence identifying lazy kinetochores as possessing a potential for erroneous segregation. This leaves 2:3% (2/85) of unperturbed RPE1 cells with an uncorrected lazy kinetochore (our study), which is consistent with the 2% of telophase RPE1 cells that contain a micronucleus (Orr et al, 2021). We have thus identified an additional layer of anaphase error correction that is consistent with independent experiments showing that inhibition of Aurora B after anaphase onset also leads to an increase in lagging chromosomes in multiple cell types including RPE1 (Orr et al, 2021).…”

“…This leaves 2:3% (2/85) of unperturbed RPE1 cells with an uncorrected lazy kinetochore (our study), which is consistent with the 2% of telophase RPE1 cells that contain a micronucleus (Orr et al, 2021). We have thus identified an additional layer of anaphase error correction that is consistent with independent experiments showing that inhibition of Aurora B after anaphase onset also leads to an increase in lagging chromosomes in multiple cell types including RPE1 (Orr et al, 2021). We propose that the midzone Aurora B gradient promotes phosphorylation of kinetochore substrates to destabilize attachments during anaphase.…”

“…However, we are not ruling out a possible contribution of anaphase spindle forces in the segregation of merotelically attached chromosomes to the correct daughter cell, potentially without the need for detachment (Cimini et al, 2004). Recently Orr et al (2021) showed how depletion of KMN network components or inhibition of anaphase Aurora B increased the rate of lagging chromosomes and micronuclei formation and thus proposed that stable microtubule-kinetochore attachments are involved in anaphase error correction. They also suggested that midzone Aurora B activity increases microtubule-kinetochore attachment stability.…”

“…They also suggested that midzone Aurora B activity increases microtubule-kinetochore attachment stability. Future work will be needed to understand the relationship between the attachment stabilization proposed by Orr et al (2021), kinetochore stabilization proposed by Papini et al (2021), and the destabilizing error correction proposed here.…”

Polar Chromosomes—Challenges of a Risky Path

“…In a set of recent studies, it was reported that the Aurora B midzone gradient mediates phosphorylation of outer kinetochore proteins even during anaphase [201], at similar sites as in pre-anaphase cells [158]. Thus, it seems that error correction mediated by Aurora B has an additional layer operating in early anaphase [194,202] (Figure 7, route 2), which could explain previous observations that the proportion of lagging chromosomes during anaphase is by an order of magnitude higher than the proportion of cells with aneuploidy in the same population [203]. Furthermore, this led to a redefinition of lagging kinetochores by introducing a new term of 'lazy' kinetochores, transiently lagging kinetochores that are quickly and efficiently corrected during the early anaphase by the Aurora B-dependent mechanism [194] (Figure 7, route 2).…”