A bifunctional kinase–phosphatase module balances mitotic checkpoint strength and kinetochore–microtubule attachment stability

Andrea Corno, Marilia H. Cordeiro, Lindsey A. Allan, Qian Wei Lim, Elena Harrington, Richard J. Smith, Adrian T. Saurin

Research output: Contribution to journalArticlepeer-review

56 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article numbere112630
Number of pages22
JournalEMBO Journal
Volume42
Issue number20
Early online date15 Sept 2023
DOIs
Publication statusPublished - 16 Oct 2023

Keywords

  • error-correction signalling
  • KNL1
  • mitotic checkpoint
  • PLK1
  • PP2A-B56

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry,Genetics and Molecular Biology
  • General Immunology and Microbiology

Fingerprint

Dive into the research topics of 'A bifunctional kinase–phosphatase module balances mitotic checkpoint strength and kinetochore–microtubule attachment stability'. Together they form a unique fingerprint.

Cite this