The copy-number and varied strength of MELT motifs in Spc105 balance the strength and responsiveness of the Spindle Assembly Checkpoint
The Spindle Assembly Checkpoint (SAC) maintains genome stability while ensuring timely anaphase onset. To maintain genome stability, it must be strong to delay cell division even if one chromosome is unattached, but for timely anaphase onset, it must promptly respond to silencing mechanisms. How the SAC meets these potentially antagonistic requirements is unclear. Here we show that the balance between SAC strength and responsiveness is determined by the number of 'MELT' motifs in the kinetochore protein Spc105/KNL1 and their Bub3-Bub1 binding affinities. Many strong MELT motifs per Spc105/KNL1 minimize chromosome missegregation, but too many delay SAC silencing and anaphase onset. We demonstrate this by constructing a Spc105 variant that trades SAC responsiveness for much more accurate chromosome segregation. We propose that the necessity of balancing SAC strength and responsiveness drives the dual evolutionary trend of the amplification of MELT motif number, but degeneration of their functionally optimal amino acid sequence.
We have included the source data for all the graphs that are included in the main as well as figure supplements.
Article and author information
National Institutes of Health (5R35-GM126983)
- Ajit P Joglekar
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Jon Pines, Institute of Cancer Research Research, United Kingdom
- Received: January 12, 2020
- Accepted: May 29, 2020
- Accepted Manuscript published: June 1, 2020 (version 1)
- Version of Record published: June 12, 2020 (version 2)
© 2020, Roy et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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