Publication Date:
2019
Description:
Plk1 inhibition compromises kinetochore integrity during chromosome segregation without activating mitotic checkpoint, thereby leading to formation of micronuclei.
Abstract
During mitosis, sister chromatids attach to microtubules which generate ~ 700 pN pulling force focused on the centromere. We report that chromatin‐localized signals generated by Polo‐like kinase 1 (Plk1) maintain the integrity of the kinetochore and centromere against this force. Without sufficient Plk1 activity, chromosomes become misaligned after normal condensation and congression. These chromosomes are silent to the mitotic checkpoint, and many lag and mis‐segregate in anaphase. Their centromeres and kinetochores lack CENP‐A, CENP‐C, CENP‐T, Hec1, Nuf2, and Knl1; however, CENP‐B is retained. CENP‐A loss occurs coincident with secondary misalignment and anaphase onset. This disruption occurs asymmetrically prior to anaphase and requires tension generated by microtubules. Mechanistically, centromeres highly recruit PICH DNA helicase and PICH depletion restores kinetochore disruption in pre‐anaphase cells. Furthermore, anaphase defects are significantly reduced by tethering Plk1 to chromatin, including H2B, and INCENP, but not to CENP‐A. Taken as a whole, this demonstrates that Plk1 signals are crucial for stabilizing centromeric architecture against tension.
Print ISSN:
1469-221X
Electronic ISSN:
1469-3178
Topics:
Biology
,
Medicine
