BubR1 N Terminus Acts as a Soluble Inhibitor of Cyclin B Degradation by APC/CCdc20 in Interphase
Open accessAbstract
BubR1 is an essential mitotic checkpoint protein with multiple functional domains. It has been implicated in mitotic checkpoint control, as an active kinase at unattached kinetochores, and as a cytosolic inhibitor of APC/C(Cdc20) activity, as well as in mitotic timing and stable chromosome-spindle attachment. Using BubR1-conditional knockout cells and BubR1 domain mutants, we demonstrate that the N-terminal Cdc20 binding domain of BubR1 is essential for all of these functions, whereas its C-terminal Cdc20-binding domain, Bub3-binding domain, and kinase domain are not. We find that the BubR1 N terminus binds to Cdc20 in a KEN box-dependent manner to inhibit APC/C activity in interphase, thereby allowing accumulation of cyclin B in G(2) phase prior to mitosis onset. Together, our results suggest that kinetochore-bound BubR1 is nonessential and that soluble BubR1 functions as a pseudosubstrate inhibitor of APC/C(Cdc20) during interphase to prevent unscheduled degradation of specific APC/C substrates.
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- Authors
- Malureanu, L. A., Jeganathan, K. B., Hamada, M., Wasilewski, L., Davenport, J., & van Deursen, J. M.
- Affiliations
- Mayo Clinic (US)
- St. Jude Children's Research Hospital (US)
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 16
- Issue
- 1
- Pages
- 118-131
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC2659634
- OpenAlex
- W2048994246
- Cited by
- 172
- References
- 34
- Citations by year
- 2026: 1 · 2025: 3 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 8 · 2019: 8 · 2018: 3 · 2017: 5 · 2016: 13 · 2015: 13 · 2014: 17 · 2013: 14 · 2012: 17
- FWCI
- 11.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Ellison Medical Foundation
- National Institutes of Health
- National Cancer Institute (CA-96985, R01CA096985)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- BubR1, CDC20, anaphase-promoting complex, cyclin B degradation, KEN box, spindle assembly checkpoint, interphase, G2 phase, Bub3, kinetochore, mitotic timing
- MeSH terms
- Animals, Cell Survival, Cells, Cultured, Chromosomes, Fibroblasts, Humans, Interphase, Spindle Apparatus, Recombinant Fusion Proteins, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Mice, Knockout, Cell Cycle Proteins, Cyclin B, Ubiquitin-Protein Ligase Complexes, Mice, Anaphase-Promoting Complex-Cyclosome, Cdc20 Proteins
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