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Abstract
Kinetochores are multi-protein complexes that power chromosome movements by tracking microtubules plus-ends in the mitotic spindle. Human kinetochores bind up to 20 microtubules, even though single microtubules can generate sufficient force to move chromosomes. Here, we show that high microtubule occupancy at kinetochores ensures robust chromosome segregation by providing a strong mechanical force that favours segregation of merotelic attachments during anaphase. Using low doses of the microtubules-targeting agent BAL27862 we reduce microtubule occupancy and observe that spindle morphology is unaffected and bi-oriented kinetochores can still oscillate with normal intra-kinetochore distances. Inter-kinetochore stretching is, however, dramatically reduced. The reduction in microtubule occupancy and inter-kinetochore stretching does not delay satisfaction of the spindle assembly checkpoint or induce microtubule detachment via Aurora-B kinase, which was so far thought to release microtubules from kinetochores under low stretching. Rather, partial microtubule occupancy slows down anaphase A and increases incidences of lagging chromosomes due to merotelically attached kinetochores.
Highlights
Kinetochores are multi-protein complexes that power chromosome movements by tracking microtubules plus-ends in the mitotic spindle
MT occupancy and inter-KT stretching have been linked to the satisfaction of the spindle assembly checkpoint (SAC) and the correction of erroneous KT–MT attachments[13]
Unclear exactly how many MTs must bind to a KT to satisfy the SAC: one study found that the SAC protein Mad[1] starts to detach from KTs at 50% MT occupancy[17], while another study found that unaligned biorientated KTs with an incomplete set of KT–MT attachments still had high levels of the SAC protein Bub[118]
Summary
Kinetochores are multi-protein complexes that power chromosome movements by tracking microtubules plus-ends in the mitotic spindle. A single depolymerizing MT can generate up to 30 pN of force[5], as little as 0.1 pN is enough to move a vertebrate chromosome in the cytoplasm[6,7,8], raising the question as to why human KTs evolved to accommodate 20 MTs. One explanation is that multiple MTs are required to stretch the sister-KTs apart: depolymerizing KT–MTs pull sister-KTs towards opposite spindle poles, increasing the inter-KT distances and stretching the centromeric chromatin. Inter-KT stretching is still thought to be the important criterion that cells use to distinguish between bi-oriented and erroneous syntelic KT–MT attachments In syntelic attachments both sister-KTs are bound by MTs oriented towards the same spindle pole, resulting in low inter-KT distances. It has been challenged in budding yeast, as cells with ubiquitously located Ipl1/ Aurora-B still correct syntelic KT–MT attachments[30]
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