PLK1 facilitates chromosome biorientation by suppressing centromere disintegration driven by BLM-mediated unwinding and spindle pulling

Addis Jones, Owen, Tiwari, Ankana, Olukoga, Tomisin, Herbert, Alex and Chan, Kok-Lung (2019) PLK1 facilitates chromosome biorientation by suppressing centromere disintegration driven by BLM-mediated unwinding and spindle pulling. Nature Communications, 10 (1). pp. 1-17. ISSN 2041-1723

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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.

Item Type: Article
Keywords: PLK1, PICH/ERCC6L, BLM, ultrafine DNA bridges, centromere DNA threads, chromosome biorientation, centromere disintegration, metaphase collapse
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Subjects: Q Science > Q Science (General) > Q0179.9 Research
Q Science > Q Science (General)
Depositing User: Chris Chan
Date Deposited: 25 Jun 2019 11:15
Last Modified: 03 Jul 2019 16:15
URI: http://sro.sussex.ac.uk/id/eprint/84533

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Project NameSussex Project NumberFunderFunder Ref
Molecular basis of inheritable DNA lesions on genome transformationG1408WELLCOME TRUST104178/Z/14/Z