Polo-like kinase 1 (PLK1) promotes centromere protection against a PICH/BLM-mediated deformation pathway
thesisposted on 2023-06-09, 19:41 authored by Owen Addis
Faithful chromosome segregation cannot be achieved without correctly aligning each chromosome pair, a process referred to as chromosome biorientation. Disabling the key mitotic kinase Polo like kinase 1 (PLK1) is known to impair multiple aspects of mitosis, particularly chromosome alignment. This is believed primarily due to unstable bipolar spindle-kinetochore attachments. However, contrary to this belief, PLK1 inactivation does not necessarily abolish metaphase establishment. Instead, it is shown to interfere with its long-term maintenance. This study has demonstrated that the failure of chromosome biorientation maintenance is driven by a previously undescribed mechanism that relies on PLK1 activity. Without active PLK1 during mitosis, BLM helicase is illegitimately recruited to and unwinds a specific centromere domain underneath the kinetochores. This recruitment is dependent on PICH translocase and leads to the impairment of centromere configuration and rigidity. Concurrently, bipolar spindle pulling forces enhance this centromere destructive pathway. During an absence of PLK1 activity, but under active spindle pulling forces, the distorted centromeric chromatin is promptly converted into an ultra-fine DNA structure. This has been referred to as ‘pre-anaphase DNA threads’, in order to distinguish them from the previously identified ultra-fine DNA bridges (UFBs) that form during anaphase. These new fragile DNA thread structures subsequently fail to withstand spindle tension. This results in centromere deformation that displays as whole-chromosome arm splitting, which has been termed as ‘centromere dislocation’. This severely damages centromere integrity, whilst also destroying normal metaphase maintenance. Therefore, PLK1 serves as a centromere guardian in order to protect centromeres against deformation, which is driven by a PICH/BLMmediated chromatin unwinding activity.
- Published version
Department affiliated with
- Sussex Centre for Genome Damage Stability Theses
InstitutionUniversity of Sussex
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