Abstract
Centromeres provide a pivotal function for faithful chromosome segregation. They serve as a foundation for the assembly of the kinetochore complex and spindle connection, which is essential for chromosome biorientation. Cells lacking Polo-like kinase 1 (PLK1) activity suffer severe chromosome alignment defects, which is believed primarily due to unstable kinetochore-microtubule attachment. Here, we reveal a previously undescribed mechanism named ‘centromere disintegration’ that drives chromosome misalignment in PLK1-inactivated cells. We find that PLK1 inhibition does not necessarily compromise metaphase establishment, but instead its maintenance. We demonstrate that this is caused by unlawful unwinding of DNA by BLM helicase at a specific centromere domain underneath kinetochores. Under bipolar spindle pulling, the distorted centromeres are promptly decompacted into DNA threadlike molecules, leading to centromere rupture and whole-chromosome arm splitting. Consequently, chromosome alignment collapses. Our study unveils an unexpected role of PLK1 as a chromosome guardian to maintain centromere integrity for chromosome biorientation.
Highlights
Centromeres provide a pivotal function for faithful chromosome segregation
We find that Polo-like kinase 1 (PLK1) can protect centromere integrity for chromosome biorientation maintenance
It is well-documented that cells cannot achieve proper chromosome alignment without PLK1 activity[6]
Summary
Centromeres provide a pivotal function for faithful chromosome segregation. They serve as a foundation for the assembly of the kinetochore complex and spindle connection, which is essential for chromosome biorientation. To achieve faithful chromosome segregation, condensed chromosomes need to be properly aligned prior to disjunction through a mitotic process called chromosome biorientation This requires a stable connection of spindle microtubules (MTs) emanating from opposite centrosomes to centromeres via the macromolecular complex of kinetochores (KTs)[2]. A single unattached chromosome can activate the spindle assembly checkpoint, inhibiting the anaphase promoting complex/cyclosome (APC/C)[3], and blocks anaphase onset[4,5] This elegant system allows cells to correct possible KT-MT attachment errors and prevent chromosome mis-segregation. Our study provides an alternative mechanism of chromosome misalignment in PLK1-defective cells It reveals a previously undescribed pathway of centromere protection during mitosis
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