A new mechanism controlling mitotic progression

  • Hit 495
  • Writer 최고관리자
  • 2017-11-22


[BK21 Plus Seminar]

▶Subject: A new mechanism controlling mitotic progression

▶Speaker: Taekyung Kim, Ph.D. (Postdoctoral Research Fellow, Department of Cellular & Molecular Medicine, UCSD)
▶Date: 4:00PM/Dec, 4(Mon.)/2017
▶Place: Room 400, Chemistry Bldg. 
The anaphase-promoting complex/cyclosome (APC/C), together with its essential coactivator Cdc20, triggers the metaphase-anaphase transition by targeting cyclin B and other substrates for degradation. Kinetochores, when not attached to the spindle, are known to restrict APC/C activation via the spindle checkpoint pathway that targets Cdc20.  Employing one-cell C. elegans embryos as a model, we have found that kinetochores also promote APC/C activation via a mechanism that also targets Cdc20. In prior work, we showed that kinetochore-localized Bub1/Bub3 complex promotes anaphase onset independently of its functions in spindle checkpoint signaling and chromosome alignment (Kim et al. J. Cell Biol. 2015; 209:507-17). Here, by monitoring cyclin B1 levels, we show that Bub1 depletion delays APC/C-Cdc20 activation. A fluorescent fusion of Cdc20 exhibits robust kinetochore localization, which is abolished by mutating a conserved motif in Bub1 that directly interacts with Cdc20. Notably, preventing kinetochore localization of Cdc20 phenocopies both effects of Bub1 depletion: it delays anaphase onset while also abolishing spindle checkpoint signaling. To address how kinetochore localization of Cdc20 promotes anaphase onset, we focused on its phosphoregulation. Cdc20 is phosphorylated on its N-terminus by Cdks and this phosphorylation reduces binding affinity for the APC/C. A non-phosphorylatable form of Cdc20 accelerated progression into anaphase and suppressed delayed anaphase onset induced by Bub1 depletion or by the Bub1 mutant that abolishes kinetochore localization of Cdc20. The non-phosphorylatable form of Cdc20 also suppressed the checkpoint-independent anaphase onset delay induced by preventing docking of protein phosphatase 1 (PP1) onto the kinetochore scaffold protein Knl1, but retained the ability to function in the spindle checkpoint. These results lead to a model in which Cdc20 at the kinetochore can adopt two fates: be dephosphorylated by Knl1-docked PP1 to promote APC/C activation or become part of the spindle checkpoint pathway to inhibit APC/C.  As PP1 localization is observed after chromosome alignment, we propose that the choice of Cdc20 fate is controlled by microtubule attachment status: at unattached kinetochores, Cdc20 is incorporated into the checkpoint pathway to inhibit APC/C whereas following attachment and PP1 recruitment, its dephosphorylation promotes APC/C activity.  We propose that this duality contributes to the tightly controlled switch-like transition from metaphase to anaphase..

▶Inquiry: Prof. Seung-Jae Lee (279-2351)

* This seminar will be given in English.
Please refrain from taking photos during seminars. *