MotoCor · Dissecting the role of microtubule motors in the correction of erroneous chromosome-microtubule attachments

Accurate chromosome distribution during mitosis requires that each pair of sister chromatids attaches to microtubules from opposite spindle poles via centromere-based kinetochores. However, incorrect kinetochore-microtubule attachments can be formed. These errors must be corrected to prevent chromosome missegregation and the resulting aneuploidy, an abnormal chromosome count characteristic of most human cancers. Error correction relies on the centromere/kinetochore-localised kinase Aurora B, which promotes the depolymerisation of kinetochore-binding microtubules in response to lack of tension within erroneous attachments. Tension locally modulates the accessibility of Aurora B to its substrates, which include the microtubule-depolymerising motor MCAK. Paradoxically, Aurora B suppresses MCAK activity and should, therefore, stabilise erroneous tensionless attachments. This contradiction nurtures the ambiguity of the long-sought error correction mechanism. Findings from the host laboratory provide new insights into this process. Microtubule poleward flux, driven by motor-mediated sliding of interpolar microtubules, suppresses MCAK depolymerising activity, potentially by generating tension within attachments. My goal is to provide a precise and integrative mechanism on how motor proteins modulate the error correction mechanism. I will focus on three key objectives: (1) identifying the flux-generating motors that create tension within attachments, (2) determining the role of tension in MCAK-mediated error correction, and (3) dissecting the tension-related interplay between Aurora B and MCAK during error correction. To achieve this, I will integrate super-resolution live cell imaging with acute protein depletion using the auxin-degron system, delivered at endogenous loci through CRISPR-Cas9. This approach will enable the monitoring of multiple motors in error correction with unprecedented spatiotemporal resolution, providing new insights into how cells prevent aneuploidy.