Abstract
During mitosis, the Spindle Assembly Checkpoint (SAC) maintains genome stability while also ensuring timely anaphase onset. To maintain genome stability, the SAC must be strong to delay anaphase even if just 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 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.
Highlights
To achieve accurate chromosome segregation, the dividing cell executes three processes prior to anaphase onset: (1) assembly of a bipolar spindle, (2) capture of unattached chromosomes by the spindle, and (3) bipolar attachment of each chromosome to microtubules emanating from opposite spindle poles
To provide a minimum amount of time to the cell for spindle formation and to prolong cell division as necessary to ensure chromosome attachment to the spindle, the eukaryotic cell uses a signaling mechanism known as the ‘Spindle Assembly Checkpoint’ (SAC)
When budding yeast and human cells are treated with high doses of the microtubule poison nocodazole, only a small fraction of the MELT motifs,~20 and~35% respectively, engage in SAC signaling, and even fewer MELT motifs are sufficient for arresting cell division (Aravamudhan et al, 2016; Vleugel et al, 2015; Vleugel et al, 2013; Zhang et al, 2014)
Summary
To achieve accurate chromosome segregation, the dividing cell executes three processes prior to anaphase onset: (1) assembly of a bipolar spindle, (2) capture of unattached chromosomes by the spindle, and (3) bipolar attachment of each chromosome to microtubules emanating from opposite spindle poles. The kinetochore produces an anaphase-inhibitory signal to delay cell division (Musacchio, 2015) To ensure both accurate chromosome segregation and timely anaphase onset, the dividing cell must ensure that SAC signaling is strong, and responsive to silencing mechanisms. When budding yeast and human cells are treated with high doses of the microtubule poison nocodazole, only a small fraction of the MELT motifs,~20 and~35% respectively, engage in SAC signaling, and even fewer MELT motifs are sufficient for arresting cell division (Aravamudhan et al, 2016; Vleugel et al, 2015; Vleugel et al, 2013; Zhang et al, 2014).
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