A bifunctional kinase-phosphatase module balances mitotic checkpoint strength and kinetochore-microtubule attachment stability.
KNL1
PLK1
PP2A-B56
error-correction signalling
mitotic checkpoint
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
16 10 2023
16 10 2023
Historique:
revised:
23
08
2023
received:
16
09
2022
accepted:
28
08
2023
medline:
23
10
2023
pubmed:
15
9
2023
entrez:
15
9
2023
Statut:
ppublish
Résumé
Two major mechanisms safeguard genome stability during mitosis: the mitotic checkpoint delays mitosis until all chromosomes have attached to microtubules, and the kinetochore-microtubule error-correction pathway keeps this attachment process free from errors. We demonstrate here that the optimal strength and dynamics of these processes are set by a kinase-phosphatase pair (PLK1-PP2A) that engage in negative feedback from adjacent phospho-binding motifs on the BUB complex. Uncoupling this feedback to skew the balance towards PLK1 produces a strong checkpoint, hypostable microtubule attachments and mitotic delays. Conversely, skewing the balance towards PP2A causes a weak checkpoint, hyperstable microtubule attachments and chromosome segregation errors. These phenotypes are associated with altered BUB complex recruitment to KNL1-MELT motifs, implicating PLK1-PP2A in controlling auto-amplification of MELT phosphorylation. In support, KNL1-BUB disassembly becomes contingent on PLK1 inhibition when KNL1 is engineered to contain excess MELT motifs. This elevates BUB-PLK1/PP2A complex levels on metaphase kinetochores, stabilises kinetochore-microtubule attachments, induces chromosome segregation defects and prevents KNL1-BUB disassembly at anaphase. Together, these data demonstrate how a bifunctional PLK1/PP2A module has evolved together with the MELT motifs to optimise BUB complex dynamics and ensure accurate chromosome segregation.
Identifiants
pubmed: 37712330
doi: 10.15252/embj.2022112630
pmc: PMC10577578
doi:
Substances chimiques
Protein Serine-Threonine Kinases
EC 2.7.11.1
Cell Cycle Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e112630Subventions
Organisme : Cancer Research UK
ID : 21229
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C47320/A21229
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 222494/Z/21/Z
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C10988/A22566
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.
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